Arylpiperazines and their use as metalloproteinase inhibiting agents (MMP)

ABSTRACT

Arylpiperazines of formula (I) useful as metalloproteinase inhibitors, especially as inhibitors of MMP 13.

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 of PCTapplication PCT/GB99/02801, filed Aug. 25, 1999, which claims priorityfrom European Application Nos. 98402144.4, filed Aug. 31, 1998, and99401351.4, filed Jun. 4, 1999, the specifications of all of which areincorporated by reference herein. PCT Application PCT/GB99/02801 waspublished under PCT Article 21(2) in English.

The present invention relates to compounds useful in the inhibition ofmetalloproteinases and in particular to pharmaceutical compositionscomprising these, as well as their use.

The compounds of this invention are inhibitors of one or moremetalloproteinase enzymes. Metalloproteinases are a superfamily ofproteinases (enzymes) whose numbers in recent years have increaseddramatically. Based on structural and functional considerations theseenzymes have been classified into families and subfamilies as describedin N. M. Hooper (1994) FEBS Letters 354:1-6. Examples ofmetalloproteinases include the matrix metalloproteinases (MMP) such asthe collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), thestromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase(MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17);the reprolysin or adamalysin or MDC family which includes the secretasesand sheddases such as TNF converting enzymes (ADAM10 and TACE); theastacin family which include enzymes such as procollagen processingproteinase (PCP), and other metalloprotenases such as aggrecanase, theendothelin converting enzyme family and the angiotensin convertingenzyme family.

Metalloproteinases are believed to be important in a plethora ofphysiological disease processes that involve tissue remodelling such asembryonic development, bone formation and uterine remodelling duringmenstruation. This is based on the ability of the metalloproteinases tocleave a broad range of matrix substrates such as collagen, proteoglycanand fibronectin. Metalloproteinases are also believed to be important inthe processing, or secretion, of biological important cell mediators,such as tumour necrosis factor (TNF); and the post translationalproteolysis processing, or shedding, of biologically important membraneproteins, such as the low affinity IgE receptor CD23 (for a morecomplete list see N. M. BHooper et al., (1997) Biochem J. 321 265-279).

Metalloproteinases have been associated with many disease conditions.Inhibition of the activity of one or more metalloproteinases may well beof benefit in these disease conditions, for example: variousinflammatory and allergic diseases such as, inflammation of the joint(especially rheumatoid arthritis, osteoarthritis and gout), inflammationof the gastro-intestinal tract (especially inflammatory bowel disease,ulcerative colitis and gastritis), inflammation of the skin (especiallypsoriasis, eczema, dermatitis); in tumour metastasis or invasion; indisease associated with uncontrolled degradation of the extracellularmatrix such as osteoarthritis; in bone resorptive disease (such asosteoporosis and Paget's disease)); in diseases associated with aberrantangiogenesis; the enhanced collagen remodelling associated withdiabetes, periodontal disease (such as gingivitis), corneal ulceration,ulceration of the skin, post-operative conditions (such as colonicanastomosis) and dermal wound healing; demyelinating diseases of thecentral and peripheral nervous systems (such as multiple sclerosis);Alzheimer's disease; and extracellular matrix remodelling observed incardiovascular diseases such as restenosis and atheroscelerosis.

A number of metalloproteinase inhibitors are known; different classes ofcompounds may have different degrees of potency and selectivity forinhibiting various metalloproteinases. We have discovered a new class ofcompounds that are inhibitors of metalloproteinases and are ofparticular interest in inhibiting MMP-13, as well as MMP-9. Thecompounds of this invention have beneficial potency and/orpharmacokinetic properties.

MMP13, or collagenase 3, was initially cloned from a cDNA libraryderived from a breast tumour [J. M. P. Freije et al. (1994) Journal ofBiological Chemistry 269(24):16766-16773]. PCR-RNA analysis of RNAs froma wide range of tissues indicated that MMP13 expression was limited tobreast carcinomas as it was not found in breast fibroadenomas, normal orresting mammary gland, placenta, liver, ovary, uterus, prostate orparotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1).Subsequent to this observation MMP13 has been detected in transformedepidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ.8(2):243-250], squamous cell carcinomas [N. Johansson et al., (1997) Am.J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola et al.,(1997) J. Invest. Dermatol. 109(2):225-231]. These results aresuggestive that MMP13 is secreted by transformed epithelial cells andmay be involved in the extracellular matrix degradation and cell-matrixinteraction associated with metastasis especially as observed ininvasive breast cancer lesions and in malignant epithelia growth in skincarcinogenesis.

Recent published data implies that MMP13 plays a role in the turnover ofother connective tissues. For instance, consistent with MMP13'ssubstrate specificity and preference for degrading type II collagen [P.G. Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768; V. Knauper elal., (1996) The Biochemical Journal 271: 1544-1550], MMP13 has beenhypothesised to serve a role during primary ossification and skeletalremodelling [M. Stahle-Backdahl et al., (1997) Lab. Invest.76(5):717-728; N. Johansson et al., (1997) Dev. Dyn. 208(3):387-397], indestructive joint diseases such as rheumatoid and osteo-arthritis [D.Wernicke et al., (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al.,(1996) J. Clin. Invest. 97(3:761-768; O. Lindy et al., (1997) ArthritisRheum 40(8):1391-1399]; and during the aseptic loosening of hipreplacements [S. Imai et al, (1998) 3. Bone Joint Surg. Br.80(4):701-710]. MMP13 has also been implicated in chronic adultperiodontitis as it has been localised to the epithelium of chronicallyinflamed mucosa human gingival tissue [V. J. Uitto et al., (1998) Am. J.Pathol 152(6): 1489-1499] and in remodelling of the collagenous matrixin chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol.109(l):96-101].

MMP9 (Gelatinase B; 92 kDa TypeIV Collagenase; 92 kDa Gelatinase) is asecreted protein which was first purified, then cloned and sequenced, in1989 (S. M. Wilhelm et al (1989) J. Biol Chem. 264 (29): 17213-17221.Pubished erratum in J. Biol Chem. (1990) 265 (36): 22570.). A recentreview of MMP9 provides an excellent source for detailed information andreferences on this protease: T. H. Vu & Z. Werb (1998) (In: MatrixMetalloproteinases. 1998. Edited by W. C. Parks & R. P. Mecham. pp115-148. Academic Press. ISBN 0-12-545090-7). The following points aredrawn from that review by T. H. Vu & Z. Werb (1998).

The expression of MMP9 is restricted normally to a few cell types,including trophoblasts, osteoclasts, neutrophils and macrophages.However, it's expression can be induced in these same cells and in othercell types by several mediators, including exposure of the cells togrowth factors or cytokines. These are the same mediators oftenimplicated in initiating an inflammatory response. As with othersecreted MMPs, MMP9 is released as an inactive Pro-enzyme which issubsequently cleaved to form the enzymatically active enzyme. Theproteases required for this activation in vivo are not known. Thebalance of active MMP9 versus inactive enzyme is further regulated invivo by interaction with TIMP-1 (Tissue Inhibitor ofMetalloproteinases-1), a naturally-occurring protein. TIMP-1 binds tothe C-terminal region of M9, leading to inhibition of the catalyticdomain of MP9. The balance of induced expression of ProMMP9, cleavage ofPro- to active MMP9 and the presence of TIMP-1 combine to determine theamount of catalytically active MMP9 which is present at a local site.Proteolytically active MMP9 attacks substrates which include gelatin,elastin, and native Type IV and Type V collagens; it has no activityagainst native Type I collagen, proteoglycans or laminins. There hasbeen a growing body of data implicating roles for MMP9 in variousphysiological and pathological processes. Physiological roles includethe invasion of embryonic trophoblasts through the uterine epithelium inthe early stages of embryonic implantation; some role in the growth anddevelopment of bones; and migration of inflammatory cells from thevasculature into tissues. Increased MMP9 expression has observed incertain pathological conditions, therebye implicating MMP9 in diseaseprocessed such as arthritis, tumour metastasis, Alzheimer's, MultipleSclerosis, and plaque rupture in atherosclerosis leading to acutecoronary conditions such as Myocardial Infarction.

In a first aspect of the invention we provide compounds of the formula I

wherein ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl,heteroaryl or heteroaralkyl ring comprising up to 12 ring atoms andcontaining one or more heteroatoms independently chosen from N, O, andS; alternatively ring B may be biphenyl; ring B may optionally be linkedto ring A by a C1-4 alkyl or a C1-4 alkoxy chain linking the 2-positionof ring B with a carbon atom alpha to X2;

each R3 is independently selected from hydrogen, halogen, NO2, COORwherein R is hydrogen or C1-6 alkyl, CN, CF3, C1-6 alkyl, —S—C1-6 alkyl,—SO—C1-6 alkyl, —SO2—C1-6 alkyl , C1-6 alkoxy and up to C10 aryloxy, nis 1,2 or 3;

P is —(CH₂)n- wherein n=0, 1, 2, or P is an alkene or alkyne chain of upto six carbon atoms; where X2 is C, P may be -Het-, —(CH[R6])n-Het-,-Het-(CH[R6]n- or -Het-(CH[R6])n-Het-, wherein Het is selected from—CO—, —S—, SO—, —SO2—, —NR6-, or —O— wherein n is 1 or 2, or P may beselected from —CO—N(R6)—, —N(R6)—CO—, —SO2—N(R6)— and —N(R6)—SO2—, andR6 is hydrogen, C1-6 alkyl up to C10 aralkyl or up to C9 heteroalkyl;

Ring A is a 5-7 membered aliphatic ring and may optionally be mono- ordi-substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, eachsubstituent being independently selected from halogen, C1-6 alkyl or anoxo group,

X1 and X2 are independently selected from N and C, where a ringsubstituent on ring A is an oxo group this is preferably adjacent a ringnitrogen atom;

Y is selected from —SO2—and —CO—;

Z is —CONHOH, Y is —CO— and Q is selected from —C(R6)(R7)—,CR6)(R7)—CH2—, —N(R6)—, and —N(R6)—CH2— wherein R6 is as defined above,and solely in relation to Q as here defined, R6 may also represent up toC10 aryl and up to C9 heteroaryl, and R7 is H, C1-6 alkyl, or togetherwith R6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 memberedring, the latter containing at least one heteroatom selected from N, O,and S;

Z is —CONHOH, Y is —SO2— and Q is selected from —C(R6)(R7)—, and—C(R6)(R7)—CH2—;

or Z is —N(OH)CHO and Q is selected from —CH(R6)—, —CH(R6)—CH2—, and—N(R6)—CH2—;

R1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10 aryl, up to C10heteroaryl, up to C12 aralkyl, or up to C12 heteroarylalkyl, alloptionally substituted by up to three groups independently selected fromNO2, CF3, halogen, C1-4 alkyl, carboxy(C1-4)alkyl, up to C6cycloalkyl,—0R4, —SR4, C1-4 alkyl substituted with —OR4, SR4 (and itsoxidised analogues), NR4, N—Y—R4, or C1-4 alkyl-Y—NR4, with the provisothat where R1 is —OH, —OR4, —SR4, or NR4, or N—Y—R4 then Z is not—N(OH)CHO, or R1 is 2,3,4,5,6-pentafluorophenyl;

R4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl or upto C9 aralkyl, each independently optionally substituted by halogen,NO2, CN, CF3, C1-6 alkyl, —S—C1-6 alkyl, —SO—C1-6 alkyl, —SO2—C1-6 alkylor C1-6 alkoxy;

R2 is H, C1-6 alkyl, or together with R1 forms a carbocyclic orheterocyclic spiro 5, 6 or 7 membered ring, the latter containing atleast one heteroatom selected from N, O, and S;

also the group Q can be linked to either R1 or R2 to form a 5, 6 or 7membered alkyl or heteroalkyl ring comprising one or more of O, S and N.

Any alkyl groups outlined above may be straight chain or branched.

Convenient values for the above groups include the following:

ring A=a 5-6 membered aliphatic ring, such as a piperazine ring, and mayoptionally be mono- or di-substituted by optionally substituted C1-6alkyl or C1-6-alkoxy, each substituent being independently selected fromhalogen, C1-6 alkyl or an oxo group;

R3=hydrogen, halogen, NO2, CF3, C1-4 alkyl, and C1-4 alkoxy, n is 1 or2, such as individually 4-fluoro, CF3, 4-chloro and 3,4-dichloro;

ring B=monocyclic or bicyclic aryl, aralkyl or heteroaryl having up to10 ring atoms, especially monocyclic aryl, aralkyl or heteroaryl havingup to 7 ring atoms, more especially monocyclic aryl or heteroaryl havingup to 6 ring atoms, such as a phenyl or pyridyl ring;

P=—(CH2)n- wherein n is 0 or 1, or —O—, or —CO—N(R6)—;

one or both of X2 and X1=N, or X1 is N, or X2 is C;

Y=—SO2—, Y=—CO—;

Q=—CH(R6)—, —CH(R6)—CH2—, and —N(R6)—CH2— wherein R6 is hydrogen or C1-6alkyl; also where Q is linked to R1 or R2 to form a C5-7 alkyl orheteroalkyl ring such as a cyclohexyl ring;

R1 hydrogen, C1-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to C11heteroarylalkyl, up to C10 aryl or heteroaryl such as up to C6 aryl; alloptionally substituted by up to three halogen atoms, or by CF3;

R2=hydrogen, or together with R1 represent a carbocyclic or heterocyclicspiro 5- or 6 membered ring, such as a tetrahydropyran ring;

R4 up to C10 aryl optionally substituted by halogen, NO2, CN, CF3, C1-6alkyl, —S—C1-6 alkyl, —SO—C1-6 alkyl, —SO2—C1-6 alkyl or C1-6 alkoxy;

Z=—CONHOH—, Z=—N(OH)CHO.

Preferred values for the above groups include the following:

R3=hydrogen, halogen such as chlorine, bromine or fluorine, NO2, CF3,methyl, ethyl, methoxy, ethoxy, particularly methoxy or fluorine;

ring B=a monocyclic aryl, aralkyl or heteroaryl ring having up to 7 ringatoms such as phenyl, biphenyl, napthyl, pyridyl, pyrimidinyl, pyrazinyland pyridazinyl, especially phenyl, pyridyl and pyrimidyl, moreespecially phenyl, 2-pyridyl and 2,4-pyrimidyl;

P=a direct bond;

both X2 and X1 are N;

Y=—SO2—;

Q=—CH2—;

R1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl,cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, pyridyl, pyridylethyl,thiophenylpropyl, bromothiophenyl, pyrimidinylethyl, pyrimidinylpropyl,pyridylethyl, pyridylpropyl or together with R2 is spirocyclohexane orspiro-4-pyran; R2 is hydrogen

Z=—N(OH)CHO.

More preferred values include R3 being halogen, the substituent ispreferably meta or para to the ring junction where ring B is an aryl orheteroaryl ring, where ring B is phenyl then especially 4-fluoro andwhere ring B is pyridyl then 3-, or 4-chloro (as appropriate);

Q=—CH2—.

Preferred combinations of Rings B and A include phenyl and piperazinyl;pyridyl and piperazinyl, and pyrimidine and piperazinyl respectively.

Particular alicyclic, fused and heterocyclic rings for ring B includeany one of

Particular rings for ring A include any one of

and its corresponding seven membered analogue(s).

It will be appreciated that the particular substitituents and number ofsubstituents on rings A and B are selected so as to avoid stericallyundesirable combinations. This also applies to rings as may be formed byR1 and Q, R2 and Q as well as R6 and R7.

Where optically active centres exist in the compounds of formula I, wedisclose all individual optically active forms and combinations of theseas individual specific embodiments of the invention, as well as theircorresponding racemates.

Specific compounds include

wherein R=phenyl or phenethyl and

wherein R=isobutyl or a spiro4-pyran ring

As previously outlined the compounds of the invention aremetalloproteinase inhibitors, in particular they are inhibitors ofMMP13. Each of the above indications for the compounds of the formula Irepresents an independent and particular embodiment of the invention.Whilst we do not wish to be bound by theoretical considerations, thecompounds of the invention are believed to show selective inhibition forany one of the above indications relative to any MMP1 inhibitoryactivity, by way of non-limiting example they may show 100-1000 foldselectivity over any MMP1 inhibitory activity.

In addition we have found that compounds of the formula 1 wherein ring Bis phenyl, pyridyl (such as 2-pyridyl or 3-pyridyl, especially2-pyridyl) ring optionally mono- or di-substituted, preferablymono-substituted, by halogen (for example chlorine ), P is a directbond; ring A is a piperazinyl or piperidinyl ring, Y is —SO2— and Q isC1-4 alkylene (for example —CH2—), especially —CH2—; R1 is as definedfor Formula 1 and is especially 2-phenylpropyl, 2-(2pyridyl)propyl,2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, phenyl, benzyloxymethyl,4-phenylbutyl, 2-phenylbutyl, or 2-(2thienyl)propyl; and Z is —N(OH)CHO;are of particular use as aggrecanase inhibitors ie. inhibitors ofaggrecan degradation. Of particular note are compounds of the formula Iwherein ring B is a phenyl, 3-methylphenyl, 4-fluorophenyl,3-chrorophenyl, 4-chlorophenyl, or 3,4-dichyorophenyl ring or5-chloro-2-pyridyl; P is a direct bond, ring A is piperidinyl orpiperazinyl especially piperazinyl, Y is SO2, Q is —CH2—, Z is —N(OH)CHOand R1 is phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene,2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or4chlorophenyloxydimethylmethylene. Also of mention are compounds of theformula I wherein ring B is phenyl monosubstituted by chlorine orfluorine, especially 4-chlorophenyl and 4-fluorophenyl; P is a directbond; ring A is piperidinyl, Y is SO2, Q is —CH2—, Z is —CONHOH and R1is hydrogen, i-butyl, or spiro-tetrahydropyranyl.

Particular compounds include

B A Y Q R1 Z 4-F—Ph PIP SO2 CH2 CH2CH(CH3)Ph RH 4-F—Ph PIP SO2 CH2PhCH2CH2CH2CH2 RH 3-Cl—Ph PIP SO2 CH2 PhCH2OCH2 RH 4-F—Ph PIP SO2 CH24-PyridylCH(CH3)CH2 RH 4-F—Ph Piperi- SO2 CH2 PhCH(CH3)CH2 RH dinyl4-F—Ph PIP SO2 CH2 (R)-2-PhCH(CH3)CH2 RH 3-Cl—Ph PIP SO2 CH23-PyridylCH(CH3)CH2 RH 3-CH3—Ph PIP SO2 CH2 Ph RH 4-F—Ph PIP SO2 CH2CH2CH(CH2CH3)Ph RH 5-Cl-2-Pyridyl PIP SO2 CH2 3-PyridylCH(CH3)CH2 RH4-F—Ph PIP SO2 CH2 2-thiophenylCH(CH3)CH2 RH 4-F—Ph PIP SO2 CH22-CH3PhCH2CH2 RH 4-F—Ph Piperi- SO2 CH2 3-PyridylCH(CH3)CH2 RH dinyl4-Br—Ph PIP SO2 CH2 PhCH(CH3)CH2 RH 4-F—Ph PIP SO2 CH2 4-F—PhCH(CH3)CH2RH 4-F—Ph PIP SO2 CH2 2-PyrazinylCH(CH3)CH2 RH

wherein PIP=piperazinyl

RH=reverse hydroxamate group

and R2=hydrogen

The compounds of the invention may be provided as pharmaceuticallyacceptable salts. These include acid addition salts suchas-hydrochloride, hydrobromide, citrate and maleate salts and saltsformed with phosphoric and sulphuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium orpotassium, an alkaline earth metal salt for example calcium ormagnesium, or organic amine salt for example triethylamine.

They may also be provided as in vivo hydrolysable esters. These arepharmaceutically acceptable esters that hydrolyse in the human body toproduce the parent compound. Such esters can be identified byadministering, for example intravenously to a test animal, the compoundunder test and subsequently examining the test animal's body fluids.Suitable in vivo hydrolysable esters for carboxy include methoxymethyland for hydroxy include formyl and acetyl, especially acetyl.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof for thetherapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt or an in vivo hydrolysable esterand pharmaceutically acceptable carrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, topical, parenteral, buccal, nasal, vaginal orrectal adminstration or by inhalation. For these purposes the compoundsof this invention may be formulated by means known in the art into theform of, for example, tablets, capsules, aqueous or oily solutions,suspensions, emulsions, creams, ointments, gels, nasal sprays,suppositories, finely divided powders or aerosols for inhalation, andfor parenteral use (including intravenous, intramuscular or infusion)sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain, or be co-administered(simultaneously or sequentially) with, one or more pharmacologicalagents of value in treating one or more disease conditions referred tohereinabove.

The pharmaceutical compositions of this invention will normally beadministered to humans so that, for example, a daily dose of 0.5 to 75mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease condition being treated accordingto principles known in the art.

Typically unit dosage forms will contain about 1 mg to 500 mg of acompound of this invention.

Therefore in a further aspect, the present invention provides a compoundof the formula (I) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof for use in a method of therapeutic treatmentof the human or animal body.

In yet a further aspect the present invention provides a method oftreating a metalloproteinase mediated disease condition which comprisesadministering to a warm-blooded animal a therapeutically effectiveamount of a compound of the formula (I) or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof

In another aspect the present invention provides a process for preparinga compound of the formula (I) or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof which process comprises

a) reacting a compound of the formula (II) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof with a compound ofthe formula (III)

wherein X₁ ^(I) represents X or a precursor of X (whether bymodification or displacement) or an activated form of X suitable forreaction with Y₁;

Y₁ represents Y, a precursor of Y, or an activated form of Y suitablefor reaction with X₁ ^(I); by way of non-limiting example, when X is Cthen X₁ may be derivatised to include a precursor of Y for reaction witha compound of formula III wherein Y^(I) is a precursor of Y;

Z^(I) represents a protected form of Z, a precursor of Z (whether bymodification or displacement of Z^(I)) or an activated form of Z;

and where Q=—CH₂)(R6)— then by reacting a compound of the formula IXwith an appropriate compound of the formula R1-CO—R2 to yield an alkeneof the formula X, which is then converted to a compound of the formulaXI wherein Z* is a hydroxylamine precursor of the group Z, and thenconverting Z* to the group Z, all as set out below:

or

b) reacting a compound of the formula (IV) ) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof with a compound ofthe formula (V).

wherein B^(I) represents a suitable ring function or substituent groupfor reaction with P^(I);

Z^(I) is as hereinbefore defined; and

P^(i) represents a suitably activated form of the linker P for reactionwith B^(I)

or where X2=N then P1 may be present on ring A rather than ring B

or, as required, the linker P may be formed by appropriate reaction ofprecursor groups P″ and P′″ provided on rings B^(I) and A respectively,or vice versa.

A compound of the formula (II) is conveniently prepared by reacting acompound of the formula (VI) with a compound of the formula (VII)

wherein B^(I) represents a suitable ring function or substituent group,X₂ ^(I) represents X or a precursor of X (whether by modification ordisplacement) or an activated form of X suitable for reaction with B^(I)and wherein B^(I) and X₂ ^(I) when reacted together provide the linker Pbetween ring A and ring B in the compound of formula (II). By way ofnon-limiting example, when X₂ is N then ring B is suitably derivatisedto introduce the linker P via B^(I), and when X₂ is C then both ring Band ring A are suitably derivatised to provide the linker P by thereaction of B^(I) and X₂ ^(I).

It will be appreciated that many of the relevant starting materials arecommercially available. In addition the following table shows details ofaldehyde intermediates and their corresponding registry numbers inChemical Abstracts.

Chemical Abstracts RCHO Registry Numbers2-methyl-2-(4-chlorophenoxy)propionaldehyde 6390-87-02-methyl-2(4-chlorophenylthio)-propionaldehyde 56421-90-04-phenoxybutyraldehyde 19790-62-6 cyclohexylacetaldehyde 5664-21-13-cyclohexylpropionaldehyde 4361-28-8 4-cyclohexylbutyraldehyde1860-41-9 3-(3-pyridyl)butyraldehyde 79240-21-43-(2-pyridyl)propionaldehyde 2057-32-1 5-phenylvaleraldehyde 36884-28-36-phenylhexanal 16387-61-4 3-phenylvaleraldehyde 34097-95-53-(2-thienyl)butyraldehyde 63362-02-7 3-(2-methylphenyl)propionaldehyde19564-40-0 3-phenyl-4-methylvaleraldehyde 54784-84-83-(2-pyrazinyl)butyraldehyde 177615-94-0 furan-2-carboxaldehyde221525-60-6 3-(4-chlorophenyl)propionaldehyde 75677-02-03-(4-fluorophenyl)propionaldehyde 63416-70-63-(4-pyridyl)propionaldehyde 120690-80-4 4-phenylbutraldehyde170650-98-3 2-pyridylcarboxaldehyde 1121-60-43-(3-pyridyl)propionaldehyde 1802-16-0 3-(2-furyl)propionaldehyde4543-51-5 4-(2-pyridyl)butyraldehyde 90943-32-14-Bromothiophene-2-carboxaldehyde 18971-75-8 cyclo pentanecarboxaldehyde872-53-7 Benzoxazole, 2-(1-piperazinyl)-(9Cl) 111628-39-8 Benzothiazole,2-(1-piperazinyl)-(9Cl) 55745-83-0 Benzoxazole,5-chloro-2-(1-piperazinyl)-(9Cl) 140233-44-9 Benzothiazole,6-chloro-2-(1-piperazinyl)-(9Cl) 153025-29-73-pyridyl-5-bromo-carboxaldehyde 113118-81-3

Aldehydes Without Chemical Abstracts Registry Numbers

3-(2-pyrimidyl) propionaldehyde. To a solution of 2-Bromopyrimidine(7.95 g, 0.05 M) in acetonitrile (150 mL) was added propargylalcohol(4.2 g, 0.075 M ), bis-(triphenylphosphine)-palladium(11)chloride (750mg, 1 mM), copper iodide (100 mg, 0.5 mM) and triethylamine (25 mL, 0.25M) and the mixture was stirred and heated at 70° C. for 2 hours. Anadditional amount of propargyl alcohol (2.1 g, 0.038 M),bis-(triphenylphosphine)-palladium(11)chloride (375 mg, 0.5 mil), andcopper iodide (50 mg, 0.25 mil) was then added to the reaction mixturewhich was stirred and heated at 70° C. for an additional 1 hour.

The reaction mixture was evaporated to dryness and the residue which waspre-adsorbed on to silica, chromatographed. Elution with ethyl acetategave 3-(2-pyrimidyl) prop-2-yn-3-ol as a yellow solid 4.45 g (66%). NMR(CDCl₃) 2.9 (1H, t), 4.5 (2H, d), 7.3 (1H, d), 8.8 (2H, t), MS found MH⁺135.

3-(2-pyrimidyl)propan-1-ol (4.45 g; 0.033 M) was dissolved in ethylacetate (140 mL), 10% Pd/C (890 mg) was added and the mixture stirredunder an atmosphere of hydrogen for 6 hours. The reaction mixture wasfiltered through Celite and the filtrate evaporated to give3-(2-pyrimidyl)propan-1-ol as a yellow oil, 4.15 g (91%). NMR (CDCl₃)2.1 (2H, m), 3.2 (2H, t), 3.8 (2H, t), 7.2 (1H, t), 8.7 (2H, d) MS foundMH⁺ 139.

3-(2-pyrimidyl)propan-1-ol was oxidized to give 3-(2-pyrimidyl)propionaldehyde as a yellow oil NMR (CDCl₃) 3.0 (2H, t), 3.4 (2H, t),7.1 (1H, t), 8.7 (2H, d), 9.9 (1H, s) using the Swern oxidationdescribed in this patent.

Using the procedure described above the following aldehydes wereprepared 4-(2-pyrimidyl) butyraldehyde by using 3-butyn-1-ol in place ofpropargylalcohol.

NMR CDCl₃ 9.8 (1H, s), 8.6 (2H, m), 7.15 (1H, m), 3.0 (2H, m), 2.5 (2H,m), 2.2 (2H, m).

4-(5-pyrimidyl)butyraldehyde by using 3-butyn-1-ol in place ofpropargylalcohol and 5-bromopyrirnidine in place of 2-bromopyrimidineNMR CDCl₃ 9.8 (1H, s), 9.1 (1H, s), 8.6 (2h, s), 2.7 (2H, t), 2.55 (2H,t), 2.0 (2H, m).

4-(2-pyridyl)butyraldehyde by using 3-butyn-1-ol in place ofpropargylalcohol and 2-bromopyridine in place of 2-bromopyrimidine.

NMR CDCl₃ 9.8 (1H, s); 8.6 (1H, d), 7.6 (1H, m); 7.1 (2H, m) 2.8 (2H,t), 2.55 (2H, t), 2.0 (2H, m).

The compounds of the invention may be evaluated for example in thefollowing assays:

Isolated Enzyme Assays

Matrix Metalloproteinase family including for example MMP13.

Recombinant human proMMP13 may be expressed and purified as described byKnauper et al. [V. Knauper et al., (1996) The Biochemical Journal271:1544-1550 (1996)]. The purified enzyme can be used to monitorinhibitors of activity as follows: purified proMMP13 is activated using1 mM amino phenyl mercuric acid (APMA), 20 hours at 21° C.; theactivated MMP13 (11.25 ng per assay) is incubated for 4-5 hours at 35°C. in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20 mMCaCl₂, 0.02 mM ZnCl and 0.05% (w/v) Brij 35 using the syntheticsubstrate7-methoxycoumarin-4-yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH₂in the presence or absence of inhibitors. Activity is determined bymeasuring the fluorescence at λex 328 nm and λem393 nm. Percentinhibition is calculated as follows: % Inhibition is equal to the[Fluorescence_(plus inhibitor)−Fluorescence_(background)] divided by the[Fluorescence_(minus inhibitor)−Fluorescence_(background)].

A similar protocol can be used for other expressed and purified pro MMPsusing substrates and buffers conditions optimal for the particular MMP,for instance as described in C. Graham Knight el al., (1992) FEBS Lett.296(3):263-266

Adamalysin Family Including for Example TNF Convertase

The ability of the compounds to inhibit proTNFα convertase enzyme may beassessed using a partially purified, isolated enzyme assay, the enzymebeing obtained from the membranes of THP-1 as described by K. M. Mohleret al., (1994) Nature 370:218-220. The purified enzyme activity andinhibition thereof is determined by incubating the partially purifiedenzyme in the presence or absence of test compounds using the substrate4′,5′-Dimethoxy-fluoresceinylSer.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-1-yl)-fluorescein)-NH₂in assay buffer (50 mM Tris HCl, pH 7.4 containing 0.1% (w/v) TritonX-100 and 2 mM CaCl₂), at 26° C. for 18 hours. The amount of inhibitionis determined as for MMP13 except λex 490 nm and λem 530 nm were used.The substrate was synthesised as follows. The peptidic part of thesubstrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene resin eithermanually or on an automated peptide synthesiser by standard methodsinvolving the use of Fmoc-amino acids andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) as coupling agent with at least a 4- or 5-fold excess ofFmoc-amino acid and HBTU. Ser¹ and Pro² were double-coupled. Thefollowing side chain protection strategy was employed; Ser¹(Bu^(t)),Gln⁵(Trityl), Arg^(8,12)(Pmc or Pbf), Ser^(9,10,11)(Trityl),Cys¹³(Trityl). Following assembly, the N-terminal Fmoc-protecting groupwas removed by treating the Fmoc-peptidyl-resin with in DMF. Theamino-peptidyl-resin so obtained was acylated by treatment for 1.5-2 hrat 70° C. with 1.5-2 equivalents of4′,5′-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman,(1980) Anal Biochem. 108:156-161) which had been preactivated withdiisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. Thedimethoxyfluoresceinyl-peptide was then simultaneously deprotected andcleaved from the resin by treatment with trifluoroacetic acid containing5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptidewas isolated by evaporation, trituration with diethyl ether andfiltration. The isolated peptide was reacted with4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, theproduct purified by RP-HPLC and finally isolated by freeze-drying fromaqueous acetic acid. The product was characterised by MALDI-TOF MS andamino acid analysis.

Natural Substrates

The activity of the compounds of the invention as inhibitors of aggrecandegradation may be assayed using methods for example based on thedisclosures of E. C. Arner et al., (1998) Osteoarthritis and Cartilage6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601and the antibodies described therein. The potency of compounds to act asinhibitors against collagenases can be determined as described by T.Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345.

Inhibition of Metalloproteinase Activity in Cell/Tissue Based ActivityTest as an Agent to Inhibit Membrane Sheddases Such as TNF Convertase

The ability of the compounds of this invention to inhibit the cellularprocessing of TNFα production may be assessed in THP-1 cells using anELISA to detect released TNF essentially as described K. M. Mohler etal., (1994) Nature 370:218-220. In a similar fashion the processing orshedding of other membrane molecules such as those described in N. M.Hooper et al., (1997) Biochem. J. 321:265-279 may be tested usingappropriate cell lines and with suitable antibodies to detect the shedprotein.

Test as an Agent to Inhibit Cell Based Invasion

The ability of the compound of this invention to inhibit the migrationof cells in an invasion assay may be determined as described in A.Albini et al., (1987) Cancer Research 47:3239-3245.

Test as an Agent to Inhibit Whole Blood TNF Sheddase Activity

The ability of the compounds of this invention to inhibit TNFαproduction is assessed in a human whole blood assay where LPS is used tostimulate the release of TNFα. Heparinized (10 Units/ml) human bloodobtained from volunteers is diluted 1:5 with medium (RPMI1640+bicarbonate, penicillin, streptomycin and glutamine) and incubated (160μl) with 20 μl of test compound (triplicates), in DMSO or appropriatevehicle, for 30 min at 37° C. in a humidified (5% CO₂/95% air)incubator, prior to addition of 20 μl LPS (E. coli. 0111:B4; finalconcentration 10 μg/ml). Each assay includes controls of diluted bloodincubated with medium alone (96 wells/plate) or a known TNFα inhibitoras standard. The plates are then incubated for 6 hours at 37° C.(humidified incubator), centrifuiged (2000 rpm for 10 min; 4° C.),plasma harvested (50-100 μl) and stored in 96 well plates at −70° C.before subsequent analysis for TNFα concentration by ELISA.

Test as in Agent to Inhibit In Vitro Cartilage Degradation

The ability of the compounds of this invention to inhibit thedegradation of the aggrecan or collagen components of cartilage can beassessed essentially as described by K. M. Bottomley e al., (1997)Biochem J. 323:483-488.

Pharmacodynamic Test

To evaluate the clearance properties and bioavailability of thecompounds of this invention an ex vivo pharmacodynamic test is employedwhich utilises the synthetic substrate assays above or alternativelyHPLC or Mass spectrometric analysis. This is a generic test which can beused to estimate the clearance rate of compounds across a range ofspecies. Animals (e.g. rats, marmosets) are dosed iv or po with asoluble formulation of compound (such as 20% w/v DMSO, 60% w/v PEG400)and at subsequent time points (e.g. 5, 15, 30, 60, 120, 240, 480, 720,1220 mins) the blood samples are taken from an appropriate vessel intoIOU heparin. Plasma fractions are obtained following centrifugation andthe plasma proteins precipitated with acetonitrile (80%w/v finalconcentration). After 30 mins at −20° C. the plasma proteins aresedimented by centrifugation and the supernatant fraction is evaporatedto dryness using a Savant speed vac. The sediment is reconstituted inassay buffer and subsequently analysed for compound content using thesynthetic substrate assay. Briefly, a compound concentration-responsecurve is constructed for the compound undergoing evaluation. Serialdilutions of the reconstituted plasma extracts are assessed for activityand the amount of compound present in the original plasma sample iscalculated using the concentration-response curve taking into accountthe total plasma dilution factor.

In Vivo Assessment Test as an Anti-TNF Agent

The ability of the compounds of this invention as ex vivo TNFαinhibitors is assessed in the rat. Briefly, groups of male WistarAlderley Park (AP) rats (180-210 g) are dosed with compound (6 rats) ordrug vehicle (10 rats) by the appropriate route e.g. peroral (p.o.),intraperitoneal (i.p.), subcutaneous (s.c.). Ninety minutes later ratsare sacrificed using a rising concentration of CO₂ and bled out via theposterior vena cavae into 5 Units of sodium heparin/ml blood. Bloodsamples are immediately placed on ice and centrifuiged at 2000 rpm for10 min at 4° C. and the harvested plasmas frozen at −20° C. forsubsequent assay of their effect on TNFα production by LPS-stimulatedhuman blood. The rat plasma samples are thawed and 175 μl of each sampleare added to a set format pattern in a 96 U well plate. Fifty μl ofheparinized human blood is then added to each well, mixed and the plateis incubated for 30 min at 37° C. (humidified incubator). LPS (25 μl;final concentration 10 μg/ml) is added to the wells and incubationcontinued for a further 5.5 hours. Control wells are incubated with 25μl of medium alone. Plates are then centrifuged for 10 min at 2000 rpmand 200 μl of the supernatants are transferred to a 96 well plate andfrozen at −20° C. for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:

Percent inhibition of TNFα=Mean TNFα (Controls)−Mean TNFα(Treated)×100/Mean TNFα (Controls).

Test as an Anti-arthritic Agent

Activity of a compound as an anti-arthritic is tested in thecollagen-induced arthritis (CIA) as defined by D. E. Trentham et al.,(1977) J. Exp. Med. 146:857. In this model acid soluble native type IIcollagen causes polyarthritis in rats when administered in Freundsincomplete adjuvant. Similar conditions can be used to induce arthritisin mice and primates.

Test as an Anti-cancer Agent

Activity of a compound as an anti-cancer agent may be assessedessentially as described in I. J. Fidler (1978) Methods in CancerResearch 15:399-439, using for example the B16 cell line (described inB. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, AmsterdamJun. 16-19 1998).

The invention will now be illustrated but not limited by the followingExamples:

EXAMPLES Example 11-[2-(N-Formyl-N-hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine

To a solution of1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine(338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added apreformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml).The mixture was stirred at room temperature for one hour. The mixturewas evaporated in vacuo and toluene (2×5 ml) was added and evaporated invacuo. The residue was taken in CH₂Cl₂-methanol (6 ml, 9:1) and silica(1 g) was added. The mixture was stirred for 18 hours. The silica wasfiltered off and rinsed with CH₂Cl₂-methanol (9:1). The residue waspurified on silica gel (eluant:CH₂Cl₂—MeOH 4%) to give the titlecompound as a light orange solid (220 mg, 61%).

¹H NMR (CDCl₃): 8.45 and 8.15⁻ (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88(m, 2H), 5.89 and 5.35 (m, 1H), 4.05 and 3.85 (m, 1H), 3.30-3.53 (m,5H), 3.20-3.10 (m, 4H); MS (ESI): 408 (M⁺), 430 (MNa⁺); EA: calculatedfor C₁₉H₂₂FN₃O₄S: C, 56.01, H, 5.44, N, 10.31, S, 7.87, Found: C, 56.01,H, 5.52, N, 10.04, S, 7.39.

The starting material was prepared as follows:

i) To a solution of 1-(4-fluorophenyl)piperazine (35 g, 194 mmol) andpyridine (17.5 ml) in dry dichloromethane (200 ml) at 0° C. was addedmethanesulfonyl chloride (20 ml , 258 mmol) dropwise. The mixture wasstirred for 3 hours at room temperature. The mixture was washed withwater and extracted with dichloromethane (2×100 ml). The organic layerswere dried with MgSO₄ and evaporated in vacuo. The residue wastriturated and washed with methanol to give1-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as whitecrystals.

¹H NMR (CDCl₃): 7.00 (m, 2H), 6.90 (m, 2H), 3.40 (m, 4H), 3.20 (m, 4H),2.83 (s, 3H).

ii) To a solution of LDA [8.5 mmol ; prepared by slow addition ofn-butyl lithium (3.5 ml, 8.5 mmol, 2.5 M in hexane) to a solution ofdiisopropylamine (860 mg, 8.5 mmol) in dry THF (5 ml) at −78° C.] at−78° C. was added a solution of1-(4-fluorophenyl)4-(methanesulfonyl)piperazine (1 g, 3.87 mmol) in THF(25 ml) dropwise. The mixture was stirred at −78° C. for 1 hour and asolution of diethylchlorophosphate (670 mg; 3.87 mmol) in THF (3 ml) wasadded. The mixture was stirred at −78° C. for 1 hour and benzaldehyde(450 mg; 4.24 mmol) in THF (3 ml) was added. The mixture was gentlywarmed to room temperature and stirred for 18 hours. The mixture waswashed with aqueous ammonium chloride and extracted with ethyl acetate.The organic layers were washed with water, brine and dried over MgSO₄.Purification of the residue on silica (eluant: dichloromethane) afforded1-(4-fluorophenyl)4(trans-β-styrenesulfonyl)piperazine as a white powder(621 mg, 46%).

¹H NMR (CDCl₃): 7.50 (m, 3H), 7.43 (m, 3H), 6.97 (m, 2H), 6.89 (m, 2H),6.71 (d, 1H, J=15.4 Hz), 3.37 (m, 4H), 3.19 (m, 4H).

iii) To a solution of1-(4-fluorophenyl)-4-(trans-β-styrenesulfonyl)piperazine (620 mg, 1.79mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50% aqueoussolution). The mixture was stirred for 18 hours. The solvent wasevaporated. The residue was dissolved in dichloromethane and washed withwater. The organic layer was dried on MgSO₄ to give1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine(730 mg).

¹H NMR (CDCl₃): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (s br,1H), 4.74 (s, 1H), 4.60 (dd, 1H, J=4 Hz, J′=8.8 Hz), 3.56 (dd, 1H, J=8.8Hz, J′=14.3 Hz), 3.40 (m, 4H), 3.19 (dd, 1H, J=4 Hz, J′=14.3 Hz), 3.12(m, 4H).

Example 2

Similarly the following compounds were obtained:

Compound Data

MS (ESI): 436 (MH⁺), 458 (MNa⁺)

MS (ESI): 400 (MH⁺), 422 (MNa⁺)

MS (ESI): 476 (MH⁺, ³⁵Cl); 498 (MNa⁺, ³⁵Cl)

MS (ESI): 422 (MNa⁺)

Example 3N-Hydroxy-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide

To a solution ofN-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide(125 mg, 0.19 mmol) in dichloromethane (2 ml) was added triethylsilane(66 μl, 0.42 mmol) and trifluoroacetic acid (150 μl). The mixture wasstirred at room temperature for 4 hours. The solvents were evaporated invacuo. The residue was purified by chromatography on silica (eluant:dichloromethane, then ethyl acetate then dichloromethane—10% MeOH) togive 35 mg of the title compound.

¹H NMR (DMSO d-6+CF₃COOD): 7.16 (m, 4H), 3.36 (m, 6H), 3.25 (m, 4H),2.45 (t, 2H, J=7.4 Hz); MS (ESI): 332 (MN⁺), 354 (MNa⁺).

The starting material was obtained as follows:

i) A solution of 3-mercaptopropionic acid (20 g, 185 mmol) in aceticacid (150 ml)-water (30 ml) at 0° C. was reacted with gaseous chlorine(preferably condensed at −78° C., 20 ml). After chlorine had distilled,the solvents were evaporated in vacuo; toluene was added and evaporatedto give 1,2-oxathiolane-5-one 2-dioxyde (36.12 g).

¹H NMR (DMSO d-6): 2.70 (t, 2H, J=7.2 Hz), 2.50 (t, 2H, J=7.2 Hz).

ii) A solution of 1,2-oxathiolane-5-one 2-dioxide (3.8 g, 28 mmol) inthionyl chloride (20 ml) and DMF (5 drops) was stirred at roomtemperature for 18 hours. The mixture was heated at 40° C. for 1 hour.The solvents were evaporated; toluene was added and evaporated in vacuoto give crude 3-chlorosulfonylpropionyl chloride (NMR purity: 70%, 3.58g).

¹H NMR (CDCl₃) 4.02 (t, 2H, J=7.2 Hz), 3.63 (t, 2H, J=7.2 Hz)

iii) To a solution of 3-chlorosulfonylpropionyl chloride (500 mg, 1.83mmol, 70% purity) and diisopropylethylamine (75 μl) in dichloromethane(5 ml) at −78° C. was added a solution ofO-dimethoxybenzyl-N-trimethoxybenzylhydroxylamine^([Ref1]) (664 mg, 1.83mmol) and diisopropylethylamine (320 μl, 1.83 mmol) in dichloromethane(5 ml) dropwise over 2 hours. After 30 minutes, a solution of1-(4-fluorophenyl)piperazine (330 mg, 1.83 mmol) anddiisopropylethylamine (320 μl , 1.83 mmol) in dichloromethane (5 ml) wasadded to the reaction mixture. The solution was warmed to roomtemperature and stirred for 2 hours. The solution was partitionedbetween dichloromethane and 1N hydrochloric acid. The organic layerswere washed with brine and dried over MgSO₄. Chromatography of theresidue on silica gel (eluant: ethyl acetate—petroleum ether: gradientfrom 50/50 to 80/20) gaveN-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide(260 mg).

MS (EI): 661 (M⁺).

Example 4 N-Hydroxy-3-[4-benzylpiperazine-1-sulfonyl]propionamide

In a manner analogous to that described in Example 3, from4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride there wasobtained the title compound.

¹H NMR (DMSO d-6+CF₃COOD): 7.50 (m, 5H), 4.41 (s, 2H), 3.78 (m, 2H),3.41 (m, 4H), 3.18 (m, 2H), 2.43 (t, 2H, J=7.1 Hz); MS (ESI): 328 (MH⁺).

Example 5N-Hydroxy-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide

To a solution ofN-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide(220 mg) in dichioromethane (4 ml) was added trifluoroacetic acid (200μl) andtriethylsilane (145 μl). The mixture was stirred at roomtemperature for 15 minutes, evaporated in vacuo and the residue waspurified on silica gel (eluant: dichloromethane-ether-methanol(80:20:0.5) to dichloromethane-methanol (80:20) to give the titlecompound (88 mg, 56%).

¹H NMR (DMSO d-6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd,1H, J=8.4 Hz, J′=14.3 Hz), 3.27 (m, 4H), 3.15 (m, 4H), 3.00 (dd, 1H, J=4Hz, J′=14.3 Hz), 2.62 (m, 1H), 1.6-1.2 (m, 3H), 0.89 (d, 3H, J=6.6 Hz),0.85 (d, 3H, J=6.6 Hz); MS (ESI): 388 (MH⁺), 410 (MNa⁺).

The starting material was obtained as follows:

i) A solution of 3-acetylthio-2-isobutylpropionic acid [obtained byMichael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g,34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol)in toluene (55 ml) was stirred for 18 hours at room temperature. Thesolvents were evaporated in vacuo. The residue was partitioned betweenethyl acetate and 5% sodium bicarbonate. The organic layer was washedwith brine and dried over MgSO₄. Purification of the residue bychromatography on silica gel (eluant: dichloromethane-ether (9:1)) gavebenzyl 3-acetylthio-2-isobutylpropionate (8.4 g).

MS (ESI): 317 (MNa⁺).

ii) A solution of benzyl 3-acetylthio-2-isobutylpropionate (588 mg, 2mmol) in acetic acid (12 ml)-water (1.6 ml) at 0° C. was reacted withgaseous chloride (prealably condensed at −78° C., 1.9 ml). Afterchlorine had distilled, the solvents are evaporated in vacuo to givecrude benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg).

MS (EI): 318 (M⁺).

iii) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg,2 mmol), 1-(4-fluorobenzyl)piperazine (378 mg, 2.1 mmol) andtriethylamine (340 μl, 2.4 mmol) in dichloromethane (15 ml) was stirredat 0° C. for 18 hours. After evaporation of the solvents, the residuewas partitioned between ethyl acetate and water. The organic layer waswashed with brine and dried over MgSO₄. After evaporation of the solventin vacuo, the residue was purified by chromatography on silica gel(eluant: dichloromethane-ether (9:1) to give benzyl3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionate (640mg).

MS (EI): 462 (M₊).

iv) A solution of benzyl3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionate (630mg) in methanol (10 ml) was hydrogenated under 40 PSI pressure for 18hours in the presence of palladium on charcoal (63 mg, 10%). Thecatalyst was removed by filtration and the solvents were removed invacuo to give3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionic acid(460 mg).

MS (ESI): 373 (MH⁺), 395 (MNa⁺).

v) To a solution of3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionic acid(230 mg, 0.62 mmol), 2,4-dimethoxybenzylhydroxylamine^([Ref 1]) (124 mg,0.68 mmol), DMAP (75 mg, 0.62 mmol) in DMF (1 ml) was addedN-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (152 mg,0.8 mmol). The mixture was stirred at room temperature for 2 days. Thereaction mixture was poured in water and extracted with ethyl acetate.The organic layer was washed with 5% sodium bicarbonate, brine and driedover MgSO₄. Purification of the residue on silica gel (eluant:dichloromethane-ether: gradient from 9/1 to 8/2) gaveN-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide(158 mg).

¹H NMR (CDCl₃): 8.21 (s, 1H), 7.30 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H),6.46 (m, 2H), 4.95 (m, 2H), 3.82 (s, 6H), 3.50 (dd, 1H, J=9 Hz, J′=14.2Hz), 3.37 (m, 4H), 3.14 (m, 4H), 2.84 (dd, 1H, J=14.2 Hz, J′=2 Hz), 2.60(m, 1H), 1.7-1.2 (m, 3H), 0.90 (m, 6H).

Example 64-4-(4-Fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-(N-hydroxyCarboxamide)

To a solution of4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylicacid (470 mg, 1.21 mmol) in dichloromethane (8 ml) was added oxalylchloride (700 mg, 5.6 mmol) and DMF (18 μl). The mixture was heated at35° C. for 1 hour. After evaporation of the solvents, the crude acidchloride dissolved in dichloromethane (4 ml) was added to a ice-cooledsolution of hydroxylamine (440 μl, 50% aqueous solution) in THF (8 ml).The mixture was stirred for 90 minutes at room temperature. Afterevaporation of the solvents, the residue was triturated indichloromethane-ether-methanol (80:20:5). The resulting solid was washedwith water and ethyl acetate and dried to give the title compound aswhite crystals (230 mg, 47%).

¹H NMR (DMSO d-6): 10.56 (s br, 1H), 8.74 (s br, 1H), 7.07 (m, 2H), 6.99(m, 2H) 3.66 (m, 2H), 3.47 (m, 2H), 3.40 (s, 2H), 3.25 (m, 4H), 3.16 (m,4H), 1.99 (m, 2H), 1.72 (m, 2H), MS (ESI): 402 (MH⁺), 424 (MNa⁺).

The starting material was prepared as follows:

(i) Thiolacetic acid (760 μl, 10 mml) and tributylphosphine (2.5 ml, 10mmol) in DMF (5 ml) was added dropwise to a ice-cooled suspension ofsodium hydride (530 mg, 60% in oil, 13 mmol) in DMF (1.5 ml) under anargon atmosphere. The mixture was stirred at 0° C. for 30 minutes. Tothe above solution was added 2,7-dioxaspiro[3,5]nonane-1-one^([Ref)^(2]) (1.4 g, 10 mmol) in DMF (10 ml). The mixture was stirred at 0° C.for 30 minutes and at room temperature for 18 hours. The reactionmixture was diluted with ether. The precipitate was filtered and driedto give 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid sodiumsalt.

¹H NMR (DMSO d-6): 3.65-3.40 (m, 4H), 2.99 (s, 2H), 2.27 (s, 3H), 1.86(m, 2H), 1.23 (m, 2H).

(ii) Using the same procedure described in Example 5 i), ii), iii), iv),v) except that no DBU was used in step 1, from4-(acetylthiomethyl)tetrahydropyran4-carboxylic acid sodium salt wasobtained4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylicacid (490 mg).

4-(acetylthiomethyl)tetrahydropyran4-(carboxylic acid benzyl ester): MS(ESI): 331 (MNa⁺); 4-(chlorosulfonylmethyl)tetrahydropyran-4-(carboxylicacid benzyl ester): MS (ESI): 354 (MNa⁺);4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylicacid benzyl ester: MS (ESI): 477 (MH⁺), 499 (MNa⁺);4-[4-(4-fluorophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylicacid: MS (ESI): 387 (MH⁺), 409 (MNa⁺).

Ref 1: B. Barlaam, A. Hamon, M. Maudet; Tetrahedron Lett, 1998,39, 7865

Ref 2: F. Hoffmann-La Roche, Agouron Pharm.; Eur. Patent Appl. EP780386.

Example 71-[2-(N-Formyl-N-hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine

To a solution of1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-phenylpiperazine (140 mg) inTHF (0.75 ml) and formic acid (0.25 ml) was added a preformed mixture offormic acid (0.58 ml) and acetic anhydride (0.29 ml). The solution wasstirred at ambient temperature for 18 hours. The mixture was evaporatedin vacuo, diluted with dichloromethane and washed with saturated aqueoussodium bicarbonate solution, dried (Na₂SO₄) and evaporated. The residuewas purified by chromatography eluting with 1% methanol indichloromethane to give 1-phenyl-(4-trans-b-styrenesulfonyl)piperazine(420 mg) as a foam (105 mg).

¹H NMR (d6-DMSO at 373K): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30(m, 3H), 7.20 (m, 2H), 6.90 (d, 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85(dd, 1H), 3.60 (dd, 1H), 3.30 (m, 4H); 3.15 (m, 4H); m/z: 390 (M+1).

The starting material was prepared as follows:

A solution of phenylpiperazine (487 mg) in dichloromethane (6 ml)containing triethylamine (0.63 ml) was added dropwise over 5 minutes totrans-b-styrenesulfonyl chloride (638 mg) in dichloromethane (4 ml). Thesolution was stirred at ambient temperature for 18 hours. The solutionwas diluted with dichloromethane and washed with water, dried (Na₂SO₄)and evaporated. The residue was purified by chromatography eluting with1% methanol in dichloromethane to give1-phenyl-(4-trans-b-styrenesulfonyl)piperazine (420 mg) as a solid.

¹H NMR (d6-DMSO): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd,2H), 6.90 (d, 2H), 6.80 (dd, 1H), 3.20 (s, 8H); m/z 329 (M+1).

To a solution of 1-phenyl-4-(trans-b-styrenesulfonyl)piperazine (108 mg)in THF (3 ml) was added hydroxylamine (0.45 ml, 50% aqueous solution).The mixture was stirred at ambient temperature for 18 hours. Solvent wasremoved in vauo and the residue dissolved in dichloromethane, washedwith water, dried (Na₂SO₄) and evaporated to give the product1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine as a foam(120 mg).

¹H NMR (d6-DMSO): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d,2H), 6.80 (dd, 1H), 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd,1H), 3.20 (m, 4H); 3.10 (m, 4H) m/z 362 (M+1).

Example 81-[2-(N-Formyl-N-hydroxyamino)-2-(quinoline-4-yl)ethane-1-sulfonyl]-4-(4-fluorophenyl)piperazine

To a suspension of1-[2-(N-hydroxyamino)-2-(quinoline-4-yl)ethane-1-sulfonyl]-4-(4-fluorophenyl)piperazine(148 mg, 0.34 mmol) in THF (2 ml)—CH₂Cl₂ (2 ml) was added5-methyl-3-formyl-1,3,4-thiadiazole-2(3H)-thione⁽¹⁾ (140 mg, 0.87 mmol).The mixture was stirred for 3 h. After addition of methanol (2 ml) andsilica (1 g), the mixture was stirred for 18 h. The solids werefiltered. The filtrates were washed with sat. NaHCO₃ and brine.Evaporation of the solvents followed by trituration inacetonitrile—CH₂Cl₂ gave the starting material (60 mg). Chromatographyof the mother liquors with acetonitrile—CH₂Cl₂ (1:1) gave the titlecompound (20 mg, 13%).

¹H-NMR (CDCl₃): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m,3H), 6.97 (m, 2H), 6.86 (m, 2H), 5.66 (m, 1H), 3.55-3.1 (m, 10H), MS(ESI): 459 (MH⁺).

The starting material was prepared from quinoline-4-carboxaldehyde and1-(fluorophenyl)-4-methanesulfonyl)piperazine in a similar manner toExample 1 ii-iii): 188 mg: MS (ESI): 431 (MH⁺); HPLC t_(R) (ColumnTSKgel super ODS 2 mm 4.6 mm×5 cm, gradient methanol/water 20 to 100% in5 min, flow rate: 1.4 ml/mn): 3.43 min.

(1) Yazawa, H.; Goto, S. Tetrahedron Lett., 1985, 26, 3703

Example 91-[1-(N-Formyl-N-hydroxyamino)-1-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazine

Similarly to Example 1, the syn and anti diastereoisomers of1-[1-(N-hydroxyamino)-1-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazinewere converted to the title compound (as 2 diastereoisomers):

diastereoisomer 1 from the less polar hydroxylamine: 36 mg, 70%; ¹H-NMR(CDCl₃): 8.45 and 8.10 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.8 (m, 2H), 5.96and 5.18 (m, 1H), 3.8-3.4 (m, 5H), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H),0.88 and 0.76 (t, 3H, J=7 Hz); MS (ESI): 540 (M{³⁵Cl, ³⁵Cl}Na⁺), 542(M{³⁷Cl, ³⁵Cl}Na⁺).

diastereoisomer 2 from the more polar hydroxylamine: 49 mg, 63%; ¹H-NMR(CDCl₃): 8.28 and 8.13 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.85 (m, 2H), 5.54and 5.02 (m, 1H), 3.45-3.9 (m, 5H), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76(t, 3H, J=7 Hz), MS (ESI): 540 (M{³⁵Cl, ³⁵Cl}Na⁺), 542 (M{³⁷Cl,³⁵Cl}Na⁺).

The starting material was prepared as follows:

Similarly to Example 1 i), from 1-(4-fluorophenyl)piperazine and1-butanesulfonyl chloride was obtained1-(4-fluorophenyl)4-(butane-1-sulfonyl)piperazine (1.84 g); similarly toExample 1 ii), this was reacted with 3,4-dichlorobenzaldehyde to give4-(4-fluorophenyl)-1-[1-(3,4-dichlorophenyl)pent-1-ene-2-sulfonyl]piperazineas a mixture of Z/E isomers (330 mg, 22%): MS (ESI): 457 (M{³⁵Cl,³⁵Cl}H⁺), 459 (M{³⁷Cl, ³⁵Cl}H⁺); similarly to Example 1 iii) except thatthe mixture was refluxed for 3 days, this was converted to1-[1-(N-hydroxyamino)-1-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazineas the syn and anti diastereoisomers.

Less polar isomer (50 mg, 15%) (TLC: eluant EtOAc—CH₂Cl₂— petroleumether (15-45-50); ¹H-NMR (CDCl₃): 7.53 (d, 1H, J=2.2 Hz), 7.46 (d, 1H,J=7.4 Hz), 7.27 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55(m, 4H), 3.16 (m, 5H), 1.75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0.77 (t,3H, J=7.4 Hz).

More polar isomer (76 mg, 23%); ¹H-NMR (CDCl₃): 7.52 (d, 1H, J=2 Hz),7.45 (d, 1H, J=8 Hz), 7.27 (m, 1H), 6.99 (m, 2H), 6.89 (m, 2H), 4.42 (m,1H), 3.55 (m, 4H), 3.41 (m, 1H), 3.14 (m, 4H), 1.6 (m, 2H), 1.25 (m,2H), 0.76 (t, 3, J=7.3 Hz).

Example 10 Trans1-[2-(N-Formyl-N-hydroxyamino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)-piperazine

Similarly to Example 1, from trans1-[2-(N-hydroxyamino)cyclohexane-1-sulfonyl]4-(4-fluorophenyl)piperazinewas obtained the title compound (68 mg, 23%).

¹H-NMR (CDCl₃): 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40and 3.92 (m, 1H), 3.35-3.55 (m, 5H), 3.15 (n, 4H), 2.35 (m, 1H), 2.0-1.8(m, 3H), 1.2-1.6 (m, 4H); MS (ESI): 408 (MNa⁺).

The starting material was obtained as follows:

i) To a solution of LDA (51 mmol, prepared by slow addition of n-butyllithium (20.4 ml, 2.5M in hexane, 51 mmol) to a solution ofdiisopropylamine (5.16 g, 51 mmol) in THF (30 ml) at −78° C.) at −78° C.was added a solution of 1-(4-fluorophenyl)4-(methanesulfonyl)-piperazine(6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 h at−78° C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF(20 ml) was added dropwise. The mixture was stirred at −78° C. for 1 hand at room temperature for 18 h. The solution was diluted with EtOAcand washed with sat. NH₄Cl and brine and dried over MgSO₄.Chromatography of the residue on silica gel (eluant: EtOAc—CH₂Cl₂—petroleum ether (15:35:50)) afforded1-(6-chloro-2-hexanone-1-sulfonyl)-4-(4-fluorophenyl)piperazine (5.22 g,60%) as white crystals: MS (ESI): 399 (MNa⁺).

ii) A mixture of this compound (5.22 g, 13.9 mmol) and NaI (42 g) inacetone (90 ml) was refluxed for 5 h. After cooling and partitioningbetween EtOAc and water, the organic layer was washed with 10% NaHSO₃and brine, and dried over MgSO₄ to give1-(6-iodo-2-hexanone-1-sulfonyl)-4-(4-fluorophenyl)piperazine (6.13 g,quantitative) as yellowish crystals: ¹H-NMR (CDCl₃): 6.98 (m, 2H), 6.88(m, 2H), 4.00 (s, 2H), 3.46 (t, 4H, J=4.8 Hz), 3.19 (t, 2H, J=6.6 Hz),3.16 (t, 4H, J=4.8 Hz), 2.79 (t, 2H, J=6.6 Hz), 1.85 (m, 2H), 1.74 (m,2H).

ii) A mixture of this compound (1.27 g, 4.85 mmol) and cesium carbonate(8 g, 24.5 mmol) in CH₂Cl₂ (90 ml) was stirred at room temperature for 4h. To the mixture was slowly added water and 2N HCl until pH˜7. Themixture was extracted with CH₂Cl₂. The organic layer was dried overMgSO₄. Chromatography on silica gel (eluant: EtOAc—petroleum ether(4:6)) afforded1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (880 mg, 53%).

¹H-NMR (CDCl₃): 6.97 (m, 2H), 6.88 (m, 2H), 3.83 (m, 1H), 3.48 (m, 4H),3.12 (m, 4H), 2.81 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), 2.2-2.0 (m, 3H),1.75 (m, 2H); MS (ESI): 363 (MNa⁺); IR: 1716.

Further elution (EtOAc—petroleum ether (6:4)) afforded1-[(tetrahydropyran-2-yl)methylidenesulfonyl]-4-(4-fluorophenyl)piperazine(630 mg, 38%): ¹H-NMR (CDCl₃) 6.98 (m, 2H), 6.87 (m, 2H), 5.21 (s, 1H),4.14 (t, 2H, J=5.2 Hz), 3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, J=6.6Hz), 1.82 (m, 4H); MS (ESI): 363 (MNa⁺).

iv) To a solution of1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (284 mg, 0.83mmol) in methanol-THF (16 ml, 3:1) at 0° C. was added sodium borohydride(3.7 mg, 1 mmol). The mixture was stirred at 0° C. for 30 min and atroom temperature for 1 h 30. The solvents were evaporated. SaturatedNH₄Cl and water were added. The precipitate was filtered, washed withwater and dried to give1-(2-cyclohexanol-1-sulfonyl)4-(4-fluorophenyl)piperazine (250 mg, 88%):MS (ESI): 343 (MH⁺).

v) To a solution of1-(2-cyclohexanol-1-sulfonyl)-4-(4-fluorophenyl)piperazine (310 mg, 0.9mmol) in THF (15 ml) was added triphenylphosphine (1.18 g ; 4.5 mmol)and DEAD (712 μl, 4.5 mmol) dropwise. The mixture was stirred at roomtemperature for 18 h. Evaporation of the solvents and purification onsilica gel (eluant: EtOAc—petroleum ether, gradient from 2:8 to 3:7)gave 1-[1-cyclohexene-1-sulfonyl]-4-(4-fluorophenyl)piperazine (285 mg,98%): MS (ESI): 325 (MH⁺).

vi) Similarly to Example 1 iii) except that the reaction was heated at65° C. for 30 h, from1-(1-cyclohexene-1-sulfonyl)-4-(4-fluorophenyl)piperazine (280 mg, 0.86mg) was obtained trans1-[2-(N-hydroxyamino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazine(270 mg, 88%): ¹H-NMR (CDCl₃): 6.98 (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H),3.34 (m, 2H), 3.14 (m, 4H), 2.30 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H),1.9-1.2 (m, 5H); MS (ESI): 358 (MH⁺).

Example 11 Cis1-[2-(N-Formyl-N-hydroxyamino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)-piperazine

Similarly to Example 1, from cis1-[2-(N-hydroxyamino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazinewas obtained the title compound (18 mg, 18%): ¹H-NMR (CDCl₃): 8.39 and8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.77 and 4.25 (m, 1H), 3.48(m, 5H), 3.13 (m, 4H), 2.25-1.3 (m, 8H); MS (ESI) 408 (MNa⁺).

The starting material was obtained as follows:

i) A mixture of1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (50 mg, 0.14mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassiumacetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70° C. for 4h. The solvents were evaporated. After partitioning between EtOAc andwater, the organic layer was washed with brine and dried over MgSO₄ togive1-[2-(N-hydroxyimino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazineas a white solid (48 mg, 94%): MS (ESI): 356 (MH⁺).

ii) To this compound (210 mg, 0.6 mmol) in a mixture of THF—acetic acid(7 ml, 1:1) was added sodium cyanoborohydride (276 mg, 4.4 mmol). Themixture was stirred at room temperature for 18 h. Water was added andthe pH was adjusted to 9. The mixture was extracted with EtOAc. Theorganic layer was washed with brine and dried over MgSO₄. Chromatographyon silica (eluant: EtOAc—petroleum ether, gradient from 1:1 to 8:2)afforded cis1-[2-(N-hydroxyamino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazine(97 mg, 45%): ¹H-NMR (CDCl₃): 6.98 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H),3.52 (m, 4H), 3.24 (dt, 1H, J_(d)=10.6 Hz, J_(t)=3.5 Hz), 3.15 (m, 4H),2.2-1.2 (m, 8H); MS (ESI): 358 (MH⁺).

Example 12

The following compounds were made using the method outlined in Example1:

Mp Mp Low High M + H B A Y Q R1 Z 117 117 492-494 4-F—Ph PIP SO2 CH22-(5-Br-thiophene) RH 128 128 409 4-F—Ph PIP SO2 CH2 3-Pyridyl RH 125125 414 4-F—Ph PIP SO2 CH2 2-thiophenyl RH 135 135 414 4-F—Ph PIP SO2CH2 3-thiophenyl RH 409 4-F—Ph PIP SO2 CH2 2-Pyridyl RH 372 4-F—Ph PIPCO N (S)—PhCH2 A 426 4-F—Ph PIP SO2 CH2 4-F—Ph RH 358* 4-F—Ph PIP SO2CH2 Gem-di-Me RH 450 4-F—Ph 2-Me—PIP SO2 CH2 PhCH2CH2 RH 498* 4-F—Ph PIPSO2 CH2 4-Cl—PhOC(Me)2 RH 129 130 389 4-Ph Piperidinyl SO2 CH2 Ph RH500-502 3,4-di-Cl—Ph PIP SO2 CH2 CH2CH(CH3)Ph RH 466 4-F—Ph PIP SO2 CH2PhOCH2CH2CH2 RH 110 110 514* 4-Cl—Ph PIP SO2 CH2 4-Cl—PhOC(Me)2 RH 138140 550-552 3,4-di-Cl—Ph PIP SO2 CH2 4-Cl—PhOC(Me)2 RH 69 70 389 Ph 4-SO2 CH2 Ph RH Piperidinyl 456 4-F—Ph PIP SO2 CH2 c-HexylCH2CH2CH2 RH 4424-F—Ph PIP SO2 CH2 CyclohexylCH2CH2 RH 139 140 407 4-F—Ph PiperidinylSO2 CH2 Ph RH 172 172 516 4-F—Ph PIP SO2 CH2 4-Cl—PhSC(Me)2 RH 517-5195-Cl-2- PIP SO2 CH2 4-Cl—PhOC(Me)2 RH Pyridyl 516-518 3-Cl—Ph PIP SO2CH2 4-Cl—PhOC(Me)2 RH 505 4-F—Ph PIP SO2 CH2 N-PhCH2-4- RH Piperidinyl104 104 548 4-F—Ph PIP SO2 CH2 4-Cl—PhSO2C(Me)2 RH 135 135 451 4-F—PhPIP SO2 CH2 3- RH PyridylCH(CH3)CH2 100 100 451 4-F—Ph PIP SO2 CH2 4- RHPyridylCH(CH3)CH2 65 65 451 4-F—Ph PIP SO2 CH2 2-yridylCH(CH3)CH2 RH 6970 449 4-F—Ph Piperidinyl SO2 CH2 PhCH(CH3)CH2 RH 54 55 436 4-F—PhPiperidinyl SO2 CH2 2-PyridylCH2CH2 RH 66 67 449-501 4-F—Ph PiperidinylSO2 CH2 4-Cl—PhOC(Me)2 RH 480 3-Cl—Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 5055 480-482 4-Cl—Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 450 4-F—Ph PIP SO2 CH2(S)-2- RH PhCH(CH3)CH2 450 4-F—Ph PIP SO2 CH2 (R)-2- RH PhCH(CH3)CH2 4673-Cl—Ph PIP SO2 CH2 3- RH PyridylCH(CH3)CH2 464 4-F—Ph PIP SO2 CH2CH2CH(CH2CH3)Ph RH 160 163 428 4-F—Ph PIP SO2 CH2 CH2c-hexyl RH 4685-Cl-2- PIP SO2 CH2 3- RH Pyridyl PyridylCH(CH3)CH2 456 4-F—Ph PIP SO2CH2 2- RH thiophenylCH(CH3)CH2 45 46 478 4-F—Ph PIP SO2 CH2PhCH2CH2CH2CH2CH2 RH 67 68 450 4-F—Ph PIP SO2 CH2 2-CH3PhCH2CH2 RH 75 76450 4-F—Ph Piperidinyl SO2 CH2 3- RH PyridylCH(CH3)CH2 69 70 510-5124-Br—Ph PIP SO2 CH2 PhCH(CH3)CH2 RH 133 135 346 4-F—Ph PIP SO2 CH2 CH3RH 465 4-F—Ph PIP SO2 CH2 CH2CH2CH(CH3)3- RH Pyr 60 63 450 4-F—Ph PIPSO2 CH2 CH(CH3)CH2Ph RH 478 4-F—Ph PIP SO2 CH2 CH2CH(Pri)Ph RH 4524-F—Ph PIP SO2 CH2 CH2CH(CH3)Pyra- RH zinyl 420 2- PIP SO2 CH2 PhCH2CH2RH Pyrimidinyl 155 157 454 6-Cl-4- PIP SO2 CH2 PhCH2CH2 RH Pyrimidinyl452 4-Cl—Ph PIP SO2 CH2 PhCH2CH2 RH 452 3-Cl—Ph PIP SO2 CH2 PhCH2CH2 RH486 3,4-di-Cl—Ph PIP SO2 CH2 PhCH2CH2 RH 453 5-Cl-2- PIP SO2 CH2PhCH2CH2 RH Pyridyl 453 3-Cl-2- PIP SO2 CH2 PhCH2CH2 RH Pyridyl 4664-Cl—Ph Homopi- SO2 CH2 PhCH2CH2 RH perazine 419 2-Pyridyl PIP SO2 CH2PhCH2CH2 RH 494 6-Cl-4- PIP SO2 CH2 3,4-di-Cl—Ph RH Pyrimidinyl 4506-MeO-4- PIP SO2 CH2 PhCH2CH2 RH Pyrimidinyl 118 120 470 6-Cl-4- PIP SO2CH2 PhCH2OCH2 RH Pyrimidinyl 493 6-Cl-2- PIP SO2 CH2 3,4-di-Cl—Ph RHPyridyl 527 5-CF3-2- PIP SO2 CH2 3,4-di-Cl—Ph RH Pyridyl 562 3-Cl-5-CF3-PIP SO2 CH2 3,4-di-Cl—Ph RH 2-Pyridyl 469 5-Cl-2- PIP SO2 CH2 PhCH2OCH2RH Pyridyl 493 5-Cl-2- PIP SO2 CH2 3,4-di-Cl—Ph RH Pyridyl 494 6-Cl-4-PIP SO2 CH2 4-CF3—Ph RH Pyrimidinyl 523 4-Me-2- PIP SO2 CH2 3,4-di-Cl—PhRH quinolyl 468 3-Cl—Ph PIP SO2 CH2 PhCH2OCH2 RH 454 2-Cl-4- PIP SO2 CH2PhCH2CH2 RH Pyrimidinyl 459 2- PIP SO2 CH2 PhCH2CH2 RH Benzoxa- zolyl475 2- PIP SO2 CH2 PhCH2CH2 RH Benzthia- zolyl 454 6-Cl-3- PIP SO2 CH2PhCH2CH2 RH Pyridazinyl 460 2-Pyridyl PIP SO2 CH2 3,4-di-Cl—Ph RH 4592-Pyridyl PIP SO2 CH2 4-CF3—Ph RH 435 2-Pyridyl PIP SO2 CH2 PhCH2OCH2 RH420 2-Pyridyl PIP SO2 CH2 2-PyridylCH2CH2 RH 509 7-Cl-2- PIP SO2 CH2PhCH2CH2 RH Benzthia- zolyl 461 2-Pyrazinyl PIP SO2 CH2 3,4-di-Cl—Ph RH460 2-Pyrazinyl PIP SO2 CH2 4-CF3—Ph RH 436 2-Pyrazinyl PIP SO2 CH2PhCH2OCH2 RH 421 2-Pyrazinyl PIP SO2 CH2 3-PyridylCH2CH2 RH 4202-Pyrazinyl PIP SO2 CH2 PhCH2CH2 RH 470 6-Cl-3- PIP SO2 CH2 PhCH2OCH2 RHPyridazinyl 136 138 420 4- PIP SO2 CH2 PhCH2CH2 RH Pyrimidinyl 4212-Pyrazinyl PIP SO2 CH2 2-PyridylCH2CH2 RH 417 5-Cl-2- PIP SO2 CH2c-Pentyl RH Pyridyl 484 5-CN-2- PIP SO2 CH2 3,4-di-Cl—Ph RH Pyridyl 4946-Cl-2- PIP SO2 CH2 2-PyridylCH2CH2 RH Benzoxa- zolyl 4-F—Ph PIP SO2 CH22-Furyl RH 437 4-F—Ph PIP SO2 CH2 3-PyridylCH2CH2 RH 437 4-F—Ph PIP SO2CH2 4-PyridylCH2CH2 RH 492 4-F—Ph PIP SO2 CH2 PhCH2CH2CH2C(Me)2 RH 470,472 4-F—Ph PIP SO2 CH2 4-Cl—PhCH2CH2 RH 450 4-F—Ph PIP SO2 CH2PhCH2CH2CH2 RH 426 4-F—Ph PIP SO2 CH2 2-FurylCH2CH2 RH 456 4-F—Ph PIPSO2 CH2 2-Thiophenyl- RH CH2CH2CH2 468 4-F—Ph PIP SO2 CH2 4-F- RHPhCH2CH2CH2 454 4-F—Ph PIP SO2 CH2 4-F—PhCH2CH2 RH 437 4-F—Ph PIP SO2CH2 2-PyridylCH2CH2 RH 509, 511 5-Cl-2- PIP SO2 CH2 4-Br-2-Thiophenyl RHPyridyl 420 2-Pyridyl PIP SO2 CH2 3-PyridylCH2CH2 RH 453, 455 3-Cl—PhPIP SO2 CH2 3-PyridylCH2CH2 RH 487, 489 3,4-di-Cl—Ph PIP SO2 CH23-PyridylCH2CH2 RH 464 4-F—Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 454, 4565-Cl-2- PIP SO2 CH2 3-PyridylCH2CH2 RH Pyridyl 466, 468 3-Cl—Ph PIP SO2CH2 PhCH2CH2CH2 RH 467, 469 5-Cl-2- PIP SO2 CH2 PhCH2CH2CH2 RH Pyridyl468, 470 6-Cl-4- PIP SO2 CH2 PhCH2CH2CH2 RH Pyrimidinyl 455, 457 2-Cl-4-PIP SO2 CH2 3-PyridylCH2CH2 RH Pyrimidinyl 455, 457 6-Cl-4- PIP SO2 CH23-PyridylCH2CH2 RH Pyrimidinyl 454, 456 3-Cl-2- PIP SO2 CH23-PyridylCH2CH2 RH Pyridyl 433 2-Pyridyl PIP SO2 CH2 PhCH2CH2CH2 RH 5035-CF3-2- PIP SO2 CH2 PhCH2OCH2 RH Pyridyl 468, 470 P2-Cl-4- PIP SO2 CH2PhCH2CH2CH2 RH Pyrimidinyl 453, 455 3-Cl—Ph PIP SO2 CH2 2-PyridylCH2CH2RH 487, 489 3,4-di-Cl—Ph PIP SO2 CH2 2-PyridylCH2CH2 RH 135 137 455, 4576-Cl-4- PIP SO2 CH2 2-PyridylCH2CH2 RH Pyrimidinyl 107 109 488 5-CF3-2-PIP SO2 CH2 2-PyridylCH2CH2 RH Pyridyl 451 4-F—Ph PIP SO2 CH2 2- RHPyridylCH2CH2CH2 120 123 452 4-F—Ph PIP SO2 CH2 2- RHPyrimidinylCH2CH2CH2 452 4-F—Ph PIP SO2 CH2 5- RH PyrimidinylCH2CH2CH2119 121 468 5-Cl-2- PIP SO2 CH2 2- RH Pyridyl PyridylCH2CH2CH2 469, 4715-Cl-2- PIP SO2 CH2 5- RH Pyridyl PyrimidinylCH2CH2CH2 131 134 469, 4715-Cl-2- PIP SO2 CH2 2- RH Pyridyl PyrimidinylCH2CH2CH2 426, 428 5-Cl-2-PIP SO2 CH2 2-Pyridyl RH Pyridyl * = M—H R2 = hydrogen PIP = piperazinylRH = reverse hydroxamate A = carboxylic acid

MS for C17H24FN3O5S (M+H) calcd 402, found 402.

The aryl/heteroarylpiperazines and piperidines used as startingmaterials were commercially available or were described in theliterature, for example

4-(4-fluorophenyl)piperidine, CAS number 37656-48-7

Piperazine, 1-[1,1′-biphenyl]-4-yl-(180698-19-5)

Piperazine, 1-[1,1′-biphenyl]-3-yl-(115761-61-0)

Piperazine, 1-(2-naphthalenyl)-(57536-91-1)

Piperazinone, 1-phenyl-(90917-86-5)

1H-1,4-Diazepine, 1-(4-chlorophenyl)hexahydro-(41885-98-7)

Quinoline, 4-methyl-2-(1-piperazinyl)-(50693-78-2)

Piperazine, 1-(4-phenoxyphenyl)-62755-61-7

Piperazine, 1-(3-chlorophenyl)

The 2-methyl4-(4-fluorophenyl)-piperazine used as starting material wasprepared as follows:

Sodium-t-butoxide (4.1 g) was added to a solution of tir-tolylphosphine(0.638 g) and palladium acetate (0.319 g) in toluene (250 mL) underargon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene(5 g) and 2-methylpiperazine (2.85 g) were added and the mixture washeated at 110° C. for 7 hours, then allowed to cool to ambienttemperature and keep at this temperature for 20 hours. The reactionmixture was filtered through Celite®, the filter cake was washed twicewith dichloromethane (2×25 mL) and the filtrate was evaporated todryness. The residue was chromatographed on silica eluting initiallywith dichloromethane and then with a mixture of dichloromethane,methanol and ammonium hydroxide (100:5:1) to give2-methyl-4-(4-fluorophenyl)-piperazine, 2.5 g.

Using this same method and 2,6-dimethylpiperazine as starting materialthere was obtained 2,6-dimethyl4-(4-fluorophenyl)-piperazine.

Piperazine, 1-[1,1′-biphenyl-4′-fluoro]-4-yl hydrochloride

tert-butoxycarbonyl piperazine, 1-[1,1′-biphenyl-4′-fluoro]-4-yl (0.712g) was stirred in a mixture of dichloromethane (10 ml) andtrifluoroacetic acid (1.0 ml) for 18 hours at ambient temperature,evaporated in vacuo to a grey solid and used without furtherpurification. The tert-butoxycarbonyl piperazine,1-[1,1′-biphenyl-4′-fluoro]-4-yl used as starting material was preparedas follows:

Sodium-t-butoxide (1.35 g) was added to a solution ofS-(−)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.046 g) andbis(dibenzylideneacetone)palladium (0.023 g ) in toluene (25 ml) underargon and then added 4-bromo-4′-fluorobiphenyl (2.5 1 g) and1-tert-butoxycarbonylpiperazine (2.2 g) and the mixture was heated at80° C. for 5 hours. The reaction mixture was filtered, filtrateevaporated in vacuo to a yellow solid which was triturated and thenfiltered from diethyl ether(20 ml) to give tert-butoxycarbonylpiperazine, 1-[1,1′-biphenyl-4′-fluoro]-4-yl, (2.67 g), mp 165-166° C.

NMR (d6-DMSO) 1.42 (s, 9H), 3.15 (m, 4H), 3.48 (m, 4H), 7.02 (d, 2H),7.22 (m, 2H), 7.51 (d, 2H), 7.63 (m, 2H); m/z 357(M+1).

Example 13

Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml.The solution was stirred at room temperature for 30 minutes and thenadded a solution ofN-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1-yl]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine(0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at roomtemperature for 18 hours. The solution was evaporated (water-bathtemperature 30° C.) and the residual gum was purified by chromatographyusing a 10 g silica isolute eluting with CH2Cl2-3% Methanol/CH12Cl2 togiveN-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide(0.178 g), 98-101° C.

NMR (d6-DMSO 373° K): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95(dd, 1H), 5.61 (vbs, 1H), 6.89 (s, 1H), 7.43 (dd, 1H), 7.60 (d, 1H),7.70 (d, 1H), 8.29 (s, 1H), 8.36 (s, 1H); m/z 494 (M+1).

Acetic anhydride (0.63 ml) was added directly to formic acid (2.48 ml).The solution was stirred at room temperature for 30 minutes and thenadded a solution ofN-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine(0.6 g) in tetrahydrofuran (10 ml). The solution was stirred at roomtemperature for 3 hours and then diluted with ethyl acetate, neutralisedthe pH with saturated aqueous sodium hydrogen carbonate solution Theethyl acetate layer was separated, dried (Na2SO4), and evaporated todryness. The residue was purified by chromatography using a 10 g silicaisolute eluting with 10% ethyl acetate/heaxane—80% ethyl acetate/hexaneand then evaporated to dryness. The resulting white solid was filteredfrom diethyl ether to giveN-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide(0.43 1 g), 211-212° C.

NMR (d6-DMSO 373° K): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95(dd, 1H), 5.58 (vbs, 1H), 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85(d, 1H), 8.10 (d, 1H), 8.13 (s, 1H); m/z 493 (M+1).

Acetic anhydride (0.48 ml) was added directly to formic acid (1.9 ml).The solution was stirred at room temperature for 30 minutes and thenadded a solution ofN-(2-(benzyloxy)-1-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl}ethyl)hydroxylamine(0.42 g) in tetrahydrofuran (5 ml). The solution was stirred at roomtemperature for 3 hours and then diluted with ethyl acetate, neutralisedthe pH with saturated aqueous sodium hydrogen carbonate solution Theethyl acetate layer was separated, dried (Na2SO4), and evaporated todryness. The residue was purified by chromatography using a 10 g silicaisolute eluting with CH2Cl25% Methanol/CH2Cl2 to giveN-(2-(benzyloxy)-1-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl-ethyl)-N-hydroxyformamide(0.233 g), 70-75° C.

NMR (d6-DMSO 373° K): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65(m, 4H), 3.66 (dd, 1H), 3.70 (dd, 1H), 4.55 (vbs, 1H), 4.55 (s, 2H),6.70 (m, 1H), 6.85 (d, 1H), 7.28 (m, H), 7.32 (m, 4H), 7.58 (m, 1H),8.17 (m, 2H), 9.45 (bs, 1H); m/z 435 (M+1).

Acetic anhydride (0.48 ml) was added directly to formic acid (1.9 ml).The solution was stirred at room temperature for 30 minutes and thenadded a solution ofN3-pyridin-2-yl-1-{[(4-pyridin-2-ylpiperazino)sulfonyl]methylpropyl)hydroxylamine(0.152 g) in tetrahydrofuran (5 ml). The solution was stirred at roomtemperature for 3 hours and then diluted with ethyl acetate, neutralisedthe pH with saturated aqueous sodium hydrogen carbonate solution Theethyl acetate layer was separated, dried (Na2SO4), and evaporated todryness. The residue was purified by chromatography using a 10 g silicaisolute eluting with CH2Cl25% Methanol/CH2Cl2 to giveN-hydroxy-N-(3-pyridin-2-yl-1-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl}propyl)formamide(0.039 g), 80-84° C.

NMR (d6-DMSO 373° K): 2.10 (m, 2H), 2.80 (m, 2H), 3.25 (dd, 1H), 3.30(m, 4H), 3.50 (dd, 1H), 3.60 (m, 4H), 4.42 (vbs, 1H), 6.70 (m, 1H), 6.85(d, 1H), 7.19 (m, 1H), 7.22 (d, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 8.10(vbs, 1H), 8.15 (m, 1H), 8.45 (m, 1H), 9.50 (vbs, 1H); m/z 420 (M+1).

Example 14N-{1-[({4-[(5-Chloropyridin-2-yl)oxy]piperidino}sulfonyl)methyl]-3-pyridin-3-ylpropyl}-N-hydroxyformamide

To a solution of1-N-[2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl]-4-O-(5-chloro-2-pyridinyl)piperidine(2.1 g, 4.18 mmol) in THF (36 ml) added a preformed mixture of formicacid (9.0 ml) and acetic anhydride (2.25 ml). The mixture was stirred atroom temperature for 18 hrs. The reaction was neutralised usingsaturated aqueous NaHCO₃ before extracting the solution with EtOAc (×2).The combined organics were dried over Na₂SO₄ and evaporated in vacuo.The residue was stirred in MeOH at room temperature for 20 hrs to removethe bis-formyl. The residue was crystallised from EtOH to afford a whitesolid (0.898 g). m.p. 130-140° C.

¹H NMR (DMSO-100° C.): 9.50 (br s, 1H), 8.43 (d, 1H), 8.39 (dd, 1H),8.15 (d, 1H), 8.13 (br s, 1H), 7.74 (dd, 1H), 7.60 (m, 1H), 7.27 (m,1H), 6.83 (d, 1H), 5.12 (m, 1H), 4.32 (br s, 1H), 3.42 (m, 3H), 3.16 (m,3H), 2.68-2.54 (m, 2H), 2.06-1.93 (m, 4H), 1.76 (m, 2H); MS (ES+): 469.2(MH⁺), 491.1 (MNa⁺); EA: calculated for C₂₀H₂₅ClN₄O₅S: C, 51.22, H,5.37, Cl, 7.56, N, 11.95, S, 6.84, Found: C, 50.92, H, 5.30, Cl, 7.55,N, 11.90, S, 6.75.

The starting material was prepared as follows:

i) NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred indry DME (200 ml), under Argon. A mixture of 2,5-dichloropyridine (8.87g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dryDME (200 ml) was added to the NaH suspension dropwise, over a period of30 minutes. After complete addition the reaction is heated to 82° C. for48 hrs, maintaining the Argon blanket. The reaction was slowly quenchedwith water before removing most of the THF. Extracted the aqueous withDCM (×3). The organic layers were dried with Na₂SO₄ and evaporated invacuo to afford 2-(4-piperidinyloxy)-5-chloropyridine as a yellow oil(12.7 g, quantitative). ¹H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81(d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46(m, 2H); MS (ES+): 213.3 (MH⁺), 225.3 (MNa⁺).

ii) To a solution 2-(4-piperidinyloxy)-5-chloropyridine(12.9 g, 0.06mol) and Et₃N (25.4 ml, 0.182 mol) in dry dichloromethane (400 ml) at 0°C. and under Argon, was added methanesulfonyl chloride (5.3 ml, 0.067mol) in dry dichloromethane (100 ml), dropwise. The mixture was stirredfor 20 hours at room temperature. The mixture was diluted withdichloromethane (250 ml), then washed with water (×3) then brine. Theorganic layers were dried with Na₂SO₄ and evaporated in vacuo. Theresidue was triturated and washed with diethylether to give2-(N-methanesulfonyl-4-piperidinyloxy)-5-chloropyridine (15.1 g) as apale yellow solid.

¹H NMR (DMSO): 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (n, 1H),3.32 (m, 2H), 3.11 (m, 2H), 2.90 (s, 3H), 2.02 (m, 2H), 1.75 (m, 2H); MS(ES+): 291.2 (MH⁺), 313.2 (MNa⁺).

iii) 2-(N-methanesulfonyl-4-piperidinyloxy)-5-chloropyridine (2.0 g,6.89 mmol) was taken into anhydrous THF (100 ml) under Argon then cooledto −78° C. before the addition of Li(TMSA) (13.8 ml of a 1.0M solutionin THF, 13.8 mmol). The mixture was stirred at −78° C. for 20 minutesand a solution of diethylchlorophosphate (1.05 ml, 7.23 mmol) was added.The mixture was stirred at −78° C. for 1 hour before 3-pyridinylpropanal(1. 12 g, 8.27 mmol) was added then stirred at −78 for a further 1 hr.The mixture was allowed to warmed to room temperature then was washedwith aqueous ammonium chloride and extracted with ethyl acetate. Theorganic layers were washed with water, brine and dried over Na₂SO₄.Purification of the residue on silica (eluant: gradient, DCM—2%MeOH/DCM) afforded2-{N-[E/Z-4(3-pyridyl)-but-1enyl]sulfonyl}4-piperidinyloxy)-5-chloropyridineas a yellow oil (2.09 g).

¹H NMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H), 8.19 (m, 1H), 7.82 (m, 1H),7.64 (m, 1H,), 7.30 (m, 1H), 6.85 (m, 1H), 6.88-6.27 (m, 2H, E/Zisomers), 5.00 (n, 1H), 3.15 (m, 2H), 2.83 (m, 5H), 2.61 (m, 1H), 1.85(m, 2H), 1.70 (m, 2H); MS (ES+): 408.1 (MH⁺), 430.2 (MNa⁺).

iv) To a solution of2-{N-[E/Z-4(3-pyridyl)-but-1enyl]sulfonyl}4-piperidinyloxy)-5-chloropyridine(2.09 g, 5.1 mmol) in THF (20 ml) was added hydroxylamine (3.4 ml, 50%aqueous solution). The mixture was stirred for 18 hours. The solvent wasevaporated. The residue was dissolved in EtOAc and washed with water(×4). The organic layer was dried on Na₂SO₄ and evaporated in vacuo togive 2-(4-piperidinyloxy)-5-chloropyridine1-N-[2-(hydroxyamino)2-(3-pyridinyl)butanesulfonyl]-4-O-(5-chloro-2-pyridinyl)piperidine(730mg).

¹H NMR (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H), 8.18 (d, 1H), 7.78 (dd, 1H),7.61 (m, 1H), 7.36 (s, 1H), 7.29 (m, 1H), 7.85 (d, 1H), 5.70 (s, 1H),5.08 (m, 1H), 3.35 (m, 3H), 3.16-3.00 (br m, 4H), 2.80-2.60 (br m, 2H),1.98 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H); MS (ES+): 441.2 (MH⁺), 463.2(MNa⁺).

Using an analogous procedure to that described in Example X, aaryl4-O-piperidine was reacted with the appropriate aldehyde to give thecompounds listed below.

MS R1 R2 R3 MW (ES⁺) Ph H 4-chlorophenyl 438 439 PhCH2CH2 H3-chlorophenyl 466.99 468 PhCH2CH2 H 3,4-dichlorophenyl 501.43 501PhCH2CH2 H 4-chlorophenyl 466.99 468 PhCH2CH2 H 5-chloro-2-pyridyl467.98 468 PhCH2CH2 H 6-chloro-4-pyrimidinyl 468.96 469 Methyl Methyl5-chloro-2-pyridyl 391.88 392 PhCH2CH2 H 2-pyridyl 433.53 434 3-pyridylH 5-chloro-2-pyridyl 440.91 441 3-pyridylCH2CH2 H 5-chloro-2-pyridyl468.96 469 2-pyridylCH2CH2 H 5-chloro-2-pyridyl 468.96 469 PhCH2OCH2 H5-chloro-2-pyridyl 483.97 484

The following aryl-4-O-piperidines have been described previously:

Piperidine, 4-(3-chlorophenoxy)-(9Cl), CAS (97840-40-9)

Piperidine, 4-(4-chlorophenoxy)-(9Cl), CAS (97839-99-1)

Pyridine, 2-(4-piperidinyloxy)-(9Cl), CAS (127806-46-6)

Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) was synthesised in thefollowing alternative route:

1) To a stirred solution 4-hydroxypiperidine(3.5 g, 0.035 mol) in drymethanol (50 ml) at 0° C., was added di-butyl dicarbonate (9.2 ml, 0.042mol) in dry methanol (50 ml), dropwise. The mixture was stirred for 20hours at room temperature. The methanol was removed and the remainingsolution was taken into Et₂O, then washed with 1M citric acid (×3) andwater (×3). The combined aqueous extracts were extracted with Et2O whichwas dried with Na₂SO₄ and evaporated in vacuo. Purification of theresidue on silica (eluant: gradient, DCM—30% MeOH/DCM ) affordedN-BOC-4-hydroxypiperidine as a yellow oil (6.4 g). ¹H NMR (DMSO): 4.05(m, 2H), 3.70-3.52 (br m, 3H), 2.92 (m, 2H), 1.66 (m, 2H), 1.40 (s, 9H),1.33-1.18 (br m, 2H); MS (ES+): 201.3 (MH⁺), 219.4 (MNH₄ ⁺).

2) To a stirred solution N-BOC-4-hydroxypiperidine(2.0 g, 0.01 mol),triphenylphosphine (3.68 g, 0.014 mol) and 3,4-dichlorophenol (1.96 g,0.012 mol) in dry toluene (75 ml) [with molecular sieves, at 0° C. andunder Argon] was added diethyl azodicarboxylate (2.52 ml, 0.016 mol),dropwise. The mixture was stirred for 1.5 hrs at 0° C. Filtered thesolution and removed the toluene before vigorously stirring in isohexane(100 ml) and filtered the resulting suspension. The filtrate was washedwith 2M aqueous NaOH (×8), dried with Na₂SO₄ and evaporated in vacuo.Purification of the residue on silica (eluant: 20% EtOAc/isohexane)afforded N-Boc-Piperidine, 4-(3,4-dichloropkenoxy)-(9Cl) as a yellowsolid (1.96 g). ¹H NMR (DMSO): 7.52 (d, 1H), 7.31 (d, 1H), 7.01 (dd,1H), 4.62 (m, 1H), 3.65 (m, 2H), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m,2H), 1.40 (s, 9H), MS (ES+): 346.3 (MH⁺), 368.4 (MNa⁺).

3) 50% aquous trifluoroacetic acid (18 ml) was added to a stirredsolution N-Boc-piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) (1.96 g, 5.66mmol). After 3.5 hrs toluene is added and evaporated in vacuo, this wasrepeated twice. The residue was then taken into EtOAc washed withsaturated aqueous NaHCO₃ (×3), dried with Na₂SO₄ and evaporated in vacuoto afforded piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) a white solid (1.3g). ¹H NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), 7.04 (dd, 1H), 4.70 (m,1H), 3.31 (m, 2H), 3.09 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H); MS (ES+):2.26.3 (MH⁺).

Piperidine, 4-(3,4-dichlorophenoxy)(9Cl) was then taken through stepsii-iv as described above.

Example 15 1 -Mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine

1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution ofmethyl 6-chloronicotinate (1.7 g) and N,N-diisopropylethylamine (6.3 ml)in dimethylacetamide (20 ml) and the mixture was heated at 120° C. for 2hours. The mixture was allowed to cool to ambient temperature and pouredonto crushed ice/water (50 ml) to precipitate a tan solid. The solid wascollected by filtration and dried at 80° C. for 18 hours in a vacuumoven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05g), mp 205-207° C.

NMR (d6-DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80 (s, 3H),6.92 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H), m/z 300 (M+1).

Using an analogous procedure 1-mesylpiperazine hydrochloride,CAS(161357-89-7), was reacted with the appropriate chloropyridine togive the following compounds.

R MW m/z (M + 1). 6-Cl-2-pyridyl 275 276 5-Cl-2-pyridyl 275 2765-CF₃-2-pyridyl 309 310 3-Cl-5-CF₃-2-pyridyl 343 344 5-CN-2-pyridyl 266267 3-Cl-2-pyridyl 275 276 5-Br-2-pyridyl 320/322

1-(6-chloropyrimidin-4-yl)-4-mesylpiperazine

A -mixture of 4,6-dichloropyrinidine (39.4 g), 1-mesylpiperazinehydrochloride (55.7 g) and triethylamine (116 ml) in ethanol (500 ml)was stirred at reflux temperature for 4 hours. The mixture was thenstirred at room temperature for 12 hours. The solid, which hadseparated, was collected by filtration, slurry washed with ethanol (2×80ml 160 ml) then with diethyl ether (150 ml), and dried to give1-(6-chloropyrimidin-4-yl)4-mesylpiperazine as a cream solid (71.9 g).mp 200-202° C.

NMR (d6-DMSO): 2.88 (s, 3H), 3.18 (m, 4H), 3.80 (m, 4H), 7.04 (s, 1H),8.38 (m, 1H); m/z 277.3 (M+1).

Using an analogous procedure 1-mesylpiperazine hydrochloride,CAS(161357-89-7), was reacted with the appropriate chloropyrimidine orchloropyridazine to give the following compounds.

R MW m/z (M + 1). 2-Cl-pyrimidin-4-yl 276 277 6-Cl-pyridazin-3-yl 276277 pyrimidin-4-yl 242 243 6-methoxy-pryrimidin-4-yl 273.1

Example 16

Acetic anhydride (19 ml) was added directly to formic acid (76 ml). Thesolution was stirred at room temperature for 30 minutes. A solution of1-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine(17.2 g) in tetrahydrofuran (85 ml) was added in portions, to the abovesolution at 27° C. over 25 minutes. The solution was stirred at roomtemperature for 1 hour. The solution was evaporated (water-bathtemperature 30° C.) and the residual gum was dissolved in ethyl acetate(500 ml). This solution was treated with saturated aqueous sodiumhydrogen carbonate solution (200 ml) and the mixture (pH8) was stirredat room temperature for 16 hours. The ethyl acetate layer was separated,washed with saturated brine (100 ml), dried (Na₂SO₄), and evaporated todryness. The residual foam was dissolved in ethanol, a solid separatedand the miixture was stirred for 2 days. The solid was collected byfiltration, slurry washed with diethyl ether (100 ml), and dried to giveN-[1-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamideas a colourless solid (12.8 g). mp 155-157° C.

Found C, 50.29, H, 5.29, Cl, 7.82, N, 15.31, and S, 6.82%. C₁₉H₂₄ClN₅O₄Srequires C, 50.27, H, 5.33, Cl, 7.81, N, 15.43, and S, 7.06%.

NMR (d6-DMSO 373° K): 1.93 (m, 1H), 2.03 (m, 1H), 2.57 (m, 1H), 2.65 (m,1H), 3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H), 3.74 (t, 4H), 4.3 (vbr, 1H), 6.90 (s, 1H), 7.19 (m, 3H), 7.27 (m, 2H), 8.1 (br, 1H), 8.38(s, 1H), 9.5 (s, 1H); m/z 454.2 (M+1).

Acetic anhydride (31.5 ml) was added directly to formic acid (126 ml).The solution was stirred at room temperature for 30 minutes. A solutionof1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine(29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was addedin portions to the above solution at 25° C. over 25 minutes. Thesolution was stirred at room temperature for 1 hour. The solution wasevaporated (water-bath temperature 30° C.) and the residual gum wasdissolved in ethyl acetate (500 ml). This solution was treated withsaturated aqueous sodium hydrogen carbonate solution (2×250 ml) and themixture (pH8) was stirred at room temperature for 16 hours. The ethylacetate layer was separated, washed with saturated brine (100 ml), dried(Na₂SO₄), and evaporated to dryness. The residual foam was dissolved inmethanol (70 ml) and the solution was stirred for 16 hours. The solutionwas evaporated to dryness (water-bath temperature 30° C.) The residualfoam was stirred in ethanol (250 ml), solid separated and the mixturewas stirred for 18 hours. The solid was collected by filtration, slurrywashed with diethyl ether (100 ml), and dried to giveN-[2-(benyloxy)-1-({[4(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide(25.5 g). mp 118-120° C.

Found C, 48.35, H, 5.09, Cl, 7.26, N, 14.73, and S, 6.78%. C₁₉H₂₄ClN₅O₅Srequires C, 48.56, H, 5.15, Cl, 7.54, N, 14.90, and S, 6.82%.

NMR (d6-DMSO 373° K): 3.23 (dd, 1H), 3.30 (t, 4H), 3.46 (dd, 1H), 3.57(dd, 1H), 3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 1H), 7.35(m, 5H), 8.15 (br, 1H), 8.38 (s, 1H), 9.48 (br, 1H); m/z 470.2 (M+1).

Acetic anhydride (0.8 ml) was added directly to formic acid (3.2 ml).The solution was stirred at room temperature for 30 minutes.

A solution of1-(5-chloro-2-pyridyl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine(0.72 g) in tetrahydrofuran (5 ml) was added to the above solution atroom temperature. The solution was stirred at room temperature for 2days. The solution was evaporated (water-bath temperature 40° C.).

The residue was dissolved in 5% methanol in dichloromethane. Silica (5 gMerck 9385) was added to the solution, the mixture was stirred for 21hours, and evaporated to dryness. The material (pre-adsorbed on thesilica) was purified by chromatography on silica (Bond Elut 10 g), using0-3% methanol in dichloromethane as eluent, to giveN-[1-({[4-(5-chloro-2-pyridyl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamideas an orange foam (0.17 g).

NMR (d6-DMSO 373° K): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m,1H), 3.20 (dd, 1H), 3.27 (m, 4H), 3.47 (dd, 1H), 3.58 (m, 4H), 4.35 (vbr, 1H), 6.88 (dd, 1H), 7.17 (m, 3H), 7.27 (m, 2H), 7.57 (dd, 1H), 8.10(s, 1H), 8.10 (br, 1H), 9.5 (s, 1H); m/z 453.3 (M+1).

Example 17

To formic acid (31.5 ml) at 0° C. was added acetic anhydride (7.9 ml).After 20 minutes this was added to the hydroxylamine (6.10 g) dissolvedin THF (80 ml) and formic acid (40 ml) and the resulting solutionstirred overnight at room temperature. The solvent was removed underreduced pressure and the residue dissolved in DCM (500 ml), washed withsaturated sodium bicarbonate solution (2×500 ml), dried and evaporatedto dryness. To the residue dissolved in DCM (10 ml) was added diethylether (100 ml) to give the product as a white solid (5.60 g) which wascollected by filtration. Mpt 168-170° C. NMR DMSOd₆ d 10.2 (br s, 1H)*;9.8 (br s, 1H)*; 8.7 (br s, 1H)*; 8.6 (br s, 1H)*; 8. 5 (d, 1H); 8.3 (m,1H); 8.1 (d, 1H); 7.9-7.8 (m, 1H); 7.6 (dd, 1H); 7.4 (dd, 1H); 6.9 (d,1H); 5.8 (m, 1H)*; 5.5 (m, 1H)*; 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3.2 (m,4H). Anal. Calcd for C₁₇H₂₀ClN₅O₄S: C, 48.0; H, 4.7; Cl, 8.3; N, 16.5;S, 7.5. Found: C, 47.9; H, 4.7, Cl, 8.4, N, 16.3; S, 7.5. MS forC₁₇H₂₀ClN₅O₄S: (M+H) calcd 426, found 426.

*rotameric signals

The oxime (31.05 g) [Tetrahedron Letters 1994, 35, 1011] was dissolvedin DCM (500 ml) and 3-pyridinecarboxaldehyde (12.09 g) was addedfollowed by anhydrous magnesium sulfate (13.6 g). After 2 days stirringat room temperature more magnesium sulfate (13.6 g) was added andstirring was continued for a further 3 days. The mixture was thenfiltered, the solvent evaporated and the residue triturated with diethylether to give the product (36.34 g) as a white solid. Mpt 174-175° C.NMR CDCl₃ d 9.0 (s, 1H); 8.9 (d, 1H); 8.7 (d, 1H); 7.7 (s, 1H); 7.4 (dd,1H); 5.6 (s, 1H); 5.3 (d, 1H); 4.9 (dd, 1H); 4.6 (dd, 1H); 4.4 (ddd 1H);4.2 (dd, 1H); 3.7 (dd, 1H); 1.5 (s, 3H); 1.4 (s, 3H); 1.4 (s, 3H); 1.3(s, 3H).

The methyl sulfonamide (14.30 g) was dissolved in THF (500 ml) andcooled to −10° C. when lithium hexamethyldisylazide (78 ml, 1.0M in THF)was added. After 30 minutes the solution was cooled to −78° C., and thenitrone (18.00 g) dissolved in THF (350 ml) was added, keeping thetemperature below −65° C. The resulting solution was stirred for 3 hoursat −78° C. when it was quenched by the addition of brine (500 ml) andthe aqueous layer extracted with ethyl acetate (3×500 ml). The combinedorganic layers were dried and evaporated to give a yellow solid whichwas triturated with ethyl acetate/isohexane (4: 1) and then purified byflash column chromatography eluting with dichloromethane/methanol (97:3)to give 1 (16.40 g) as a white solid. Mpt 209-211° C. (dec). NMR CDCl₃ d8.6 (s, 1H); 8.4 (d, 1H); 8.1 (d, 1H); 7.8 (d, 1H); 7.5 (br s, 1H); 7.4(dd, 1H); 7.3 (dd, 1H); 6.6 (d, 1H); 4.9 (d, 1H); 4.8 (s, 1H); 4.7-4.6(m, 2H); 4.2-4.1 (m, 3H); 3.8 (dd, 1H); 3.6 (dd, 1H); 3.5-3.4 (m, 5H);3.3-3.2 (m, 4H); 1.4 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H).

To a solution of hydroxylamine 2 (14.90 g,) in ethanol (300 ml) wasadded water (220 ml) followed by 0-benzylhydroxylamine hydrochloride(13.9 1 g) and sodium bicarbonate (6.95 g). Heating gave a solutionwhich was stirred overnight at 80° C. The ethanol was removed underreduced pressure and the residue separated between water (500 ml) andethyl acetate (500 ml). The aqueous layer was washed with ethyl acetate(2×500 ml), and the combined organic layers were dried and evaporated togive a residue which was triturated with dichloromethane (100 ml) togive 3 (6.10 g) as a white solid. The mother liquor was purified byflash column chromatography eluting with ethyl acetate followed bydichloromethane 1 methanol (96:4) to give further 3 (0.85 g). Mpt170-173° C. NMR DMSOd₆ d 8.6 (s, 1H); 8.5 (d, 1H); 8.1 (d, 1H); 7.8 (d,1H); 7.6 (dd, 1H); 7.6 (s, 1H); 7.3 (dd, 1H); 6.9 (d, 1H); 6.1 (br s,1H); 4.3 (br s, 1H); 3.7-3.4 (m, 6H); 3.2-3.1 (m, 4H).

Example 18

The following compounds were made using the method outlined in Example 7

Mp Mp Low High M + H B A Y Q R1 Z 403 4-PhCH2 Piperidinyl SO2 CH2 Ph RH357 4-HCOO Piperidinyl SO2 CH2 Ph RH PhNCO Piperidinyl SO2 CH2 Ph RH 128131 412 t-ButylNCO Piperidinyl SO2 CH2 Ph RH 122 124 446 PhCH2NCOPiperidinyl SO2 CH2 Ph RH 129 131 423 c-PentylNCO Piperidinyl SO2 CH2 PhRH 390 Ph PIP SO2 CH2 Ph RH 420 4-MeO—Ph PIP SO2 CH2 Ph RH 435 4-NO2—PhPIP SO2 CH2 Ph RH 404 4-CH3—Ph PIP SO2 CH2 Ph RH 424 2-Cl—Ph PIP SO2 CH2Ph RH 420 2-OMe—Ph PIP SO2 CH2 Ph RH 424 3-Cl—Ph PIP SO2 CH2 Ph RH 4583-CF3—Ph PIP SO2 CH2 Ph RH 424 4-Cl—Ph PIP SO2 CH2 Ph RH 420 3-OMe—PhPIP SO2 CH2 Ph RH 458 3,4-di-Cl—Ph PIP SO2 CH2 Ph RH 438 4-Cl—PhCH2 PIPSO2 CH2 Ph RH 452 4-Cl—PhCO PIP SO2 CH2 Ph RH 472 4-F—PhSO2 PIP SO2 CH2Ph RH 436 5-NO2-2-Pyridyl PIP SO2 CH2 Ph RH 432 PhCH2CO PIP SO2 CH2 PhRH 504 2-NaphthylSO2 PIP SO2 CH2 Ph RH 467 4-Ph—Ph PIP SO2 CH2 Ph RH 3922-Pyrazinyl PIP SO2 CH2 Ph RH 391 2-Pyridyl PIP SO2 CH2 Ph RH 396Cyclohexyl PIP SO2 CH2 Ph RH 466 3-Ph—Ph PIP SO2 CH2 Ph RH 458 4-CF3—PhPIP SO2 CH2 Ph RH 467 4-Cl—PhNCO PIP SO2 CH2 Ph RH 440 2-Naphthyl PIPSO2 CH2 Ph RH 356 n-Propyl PIP SO2 CH2 Ph RH 448 4-Piperonyl-CH2— PIPSO2 CH2 Ph RH 460 4-t-Butyl-PhCH2— PIP SO2 CH2 Ph RH 55 60 439 4-Cl—PhOPiperidinyl SO2 CH2 Ph RH 391 4-Pyridyl PIP SO2 CH2 Ph RH 4844′-F-4-Ph—Ph PIP SO2 CH2 Ph RH 482 4-Ph—O—Ph PIP SO2 CH2 Ph RH 404 4-Ph3-OxoPIP SO2 CH2 Ph RH 449 5-CO2Me-Pyridyl PIP SO2 CH2 Ph RH 5012-PyridylNCO Piperidinyl SO2 CH2 3,4-di-Cl—Ph RH 535 5-Cl-2-PyridylNCOPiperidinyl SO2 CH2 3,4-di-Cl—Ph RH 534 4-Cl—PhNCO Piperidinyl SO2 CH23,4-di-Cl—Ph RH 500 PhNCO Piperidinyl SO2 CH2 3,4-di-Cl—Ph RH * = M—H R2= hydrogen PIP = piperazinyl RH = reverse hydroxamate

The starting material was prepared as follows:

The addition of hydroxylamine to1-trans-β-styrenesulfonyl-piperidine-4-(N-phenylcarboxamide) and thesubsequent formylation of the product was carried out as described inExample 7.

Dimethylformamide (2 drops) was added to a suspension of1-trans-β-styrenesulphonyl-piperidine-4-carboxylic acid (0.75 g) andoxalyl chloride (0.23 mL) in dichloromethane (10 mL) and was stirred for2 hours. The reaction mixture was evaporated to dryness, re-dissolved indichloromethane (10 mL) and evaporated to dryness again. The residueobtained was dissolved in dichloromethane (4 mL) and a mixture ofaniline (0.23 mL) and triethylamine (0.35 mL) was added dropwise. Themixture was stirred for 20 hours and was washed with dilute 2Mhydrochloric acid, water, aqueous saturated sodium bicarbonate solutionand water and dried Removal of the solvent gave1-trans-β-styrenesulphonyl-piperidine-4-(N-phenylcarboxamide), 0.89 g

Using the method described above there were prepared the following1-trans-β-styrenesulphonyl-piperidine-4-carboxamides

438 437(M − 1)

439 440(M + 1)

473 472(M − 1)

472 471(M − 1)

A solution of ethyl piperidinecarboxylate (3.99 g) in a mixture of THF(30 mL) and methanol (6 mL) was treated with aqueous sodium hydroxidesolution (20 mL of 2M NaOH) and the mixture stirred for 3 hours,evaporated to small volume and acidified to pH 5 with dilute 2Mhydrochloric acid. The mixture obtained was extracted with ethyl acetate(2×25 mL), the ethyl acetate extracts were washed with water, dried andevaporated to dryness to give1-trans-β-styrenesulphonyl-piperidine-4-carboxylic acid, 2.64 g.

A solution of ethyl piperidine-4-carboxate (3.0 mL) and triethylamine(2.7 mL) in dichloromethane (10 mL) was added dropwise to a cooled (icebath) solution of trans-β-styrenesulphonyl chloride (3.95 g) indichloromethane (10 mL). The reaction mixture was allowed to warm toambient temperature and stirring was continued for 20 hours. Thereaction mixture was evaporated to dryness, the residue was diluted withwater and extracted with ethyl acetate (2×25 mL). The combined ethylacetate extracts were washed with brine and dried (MgSO4) to giveethyl-(1-trans-β-styrenesulphonyl)-piperidine-4-carboxylate 5.76 g,M+H=324.

An alternative procedure for the preparation of1-trans-β-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylic acid maybe used:

To a solution of 1-trans-β-3,4dichlorostyrenesulphonylchloride (2.7 g)and isonipecotic acid (1.41 g) in acetonitrile (115 m) was added 2Msodium hydroxide (11 ml) and stirred at ambient temperature for 1 hour.The reaction mixture was acidified to pH 3 with 2M hydrochloric acid andextracted with ethyl acetate (2×15 ml), the ethyl acetate extracts weredried (Na₂SO₄), fitered and evaporated to give1-trans-β-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylate (2.67 g),m/z 364 (M+1).

Example 19

The following compounds were prepared

M + H B A Y Q R1 Z 4-F—Ph PIP SO2 CH2 i-Propyl RH 360 4-F—Ph PIP SO2 CH2Ethyl RH 386 4-F—Ph PIP SO2 CH2 spiro-c-pentyl RH 450.8 4-F—Ph PIP SO2CH2 4-NMe2—Ph RH 442 4-F—Ph PIP SO2 CH2 4-Cl—Ph RH 388 4-F—Ph PIP SO2CH2 tert-Butyl RH 442 4-F—Ph PIP SO2 CH2 2-Cl—Ph RH 484 4-F—Ph PIP SO2CH2 4-Ph—Ph RH 468 4-F—Ph PIP SO2 CH2 2,4-di-OMe—Ph RH 452.9 4-F—Ph PIPSO2 CH2 3-NO2—Ph RH 475.9 4-F—Ph PIP SO2 CH2 4-CF3—Ph RH 475.9 4-F—PhPIP SO2 CH2 2-CF3—Ph RH 374 4-F—Ph PIP SO2 CH2 Propyl RH 458 4-F—Ph PIPSO2 CH2 1-Naphthyl RH 387.9 4-F—Ph PIP SO2 CH2 3-Furyl RH 450.9 4-F—PhPIP SO2 CH2 CH2CH2SCH3 RH 388 4-F—Ph PIP SO2 CH2 iso-Butyl RH 491.84-F—Ph PIP SO2 CH2 4-Br-2-Thiophenyl RH 485.8 4-F—Ph PIP SO2 CH2 3-Br—PhRH 458 4-F—Ph PIP SO2 CH2 2-Naphthyl RH 496 4-F—Ph PIP SO2 CH22-Fluorenyl RH 466 4-F—Ph PIP SO2 CH2 4-CO2Me—Ph RH 414 4-F—Ph PIP SO2CH2 Cyclohexyl RH 402 4-F—Ph PIP SO2 CH2 2-neopentyl RH 533.9 4-F—Ph PIPSO2 CH2 3-(4-Cl—PhO)—Ph RH 452 4-F—Ph PIP SO2 CH2 PhCH2OCH2 RH 507.94-F—Ph PIP SO2 CH2 2-(5-4′-Cl—Ph)Furyl RH 450 4-F—Ph PIP SO2 CH2CH2CH(CH3)Ph RH 451.9 4-F—Ph PIP SO2 CH2 4-Piperonyl RH 4-F—Ph PIP SO2CH2 3-(OCH2Ph)Ph RH 4-F—Ph PIP SO2 CH2 4-(OCH2Ph)Ph RH 4-F—Ph PIP SO2CH2 3-CF3—Ph RH 497.9 4-F—Ph PIP SO2 CH2 C6F5 RH PIP = piperazinyl Z =reverse hydroxamate group R2 = hydrogen

Example 20

We provide NMR data for the following compounds:

(DMSO) 9.6 (1H, s), 8.5 (1H, m), 8.4 and 7.9 (1H, s), 7.7 (1H, m), 7.2(2H, m), 7.1 (2H, m), 7.0 (2H, m), 4.7 and 4.2 (1H, broad m), 3.4 (1H,m), 3.3 (5H, m), 3.1 (4H, m), 2.7 (2H, m), 2.1 (2H, m).

(DMSO) 9,8 and 9.5 (1H, broad s), 8.3 and 8.0 (1H, s), 8.1 (1H, d), 7.6(1H, dd), 7.2 (5H, m), 6.9 (1H, d), 4.7 and 4.1 (1H broad m), 3.6 (4H,m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.6 (2H, m), 1.6 (4H, m).

(DMSO) 9.6 (1H, broad S), 8.4 (1H, m), 8.3 and 7.9 (1H, s), 8.1 (1H, d),7.6 (2H, m), 7.2 (1H, d), 7.1 (1H, m), 6.9 (1H, d), 4.7 and 4.1 (1H,broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.7 (2H,m), 2.0 (2H, m).

(DMSO) 9.7 (1H, broad s), 8.5 (1H, m), 8.4 (1H, m), 8.1 and 7.9 (1H, s),7.6 (1H, m), 7.2 (2H, m), 7.0 (1H, m), 4.6 and 4.1 (1H, broad m), 3.7(4H, m), 3.4 (1H, m), 3.3 (5H, m), 2.7 (2H, m), 2.0 (2H, m).

(DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (1H, m),7.0 (1H, m), 4.0-4.2 (2H, m), 3.6 (4H, br m), 3.4-3.2 (6H, br m), 2.0(2H, br m).

(DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (1H, br s), 7.8 (1H, br), 7.6 (1H,m), 7.4 (1H, m), 6.9 (1H, m), 3.6 (4H, br m), 3.2 (6H, br m).

10.0 (1H, s), 8.5 (2H, m), 8.4 and 8.0 (1H, s), 7.9 (1H, m), 7.7 (1H,m), 7.3 (1H, m), 7.1 (1H, m), 3.7 (4H, br m), 3.45 (2H, m), 3.3 (4H, brm), 2.75 (3H, m), 2.1 (2H, m).

(DMSO) 10.0 (1H, br s), 8.6 (2H, m), 8.2 (1H, d), 7.2 (1H, m), 6.9 (4H,m), 4.9 and 4.2 (1H, br), 3.4 (6H, m), 3.0 (6H, m), 1.9 (4H, m).

(DMSO) 9.8 (1H, br), 8.7 (2H, m), 8.3 and 7.9 (1H, s), 8.1 (2H, s), 7.6(1H, m), 7.3 (1H, m), 6.9 (1H, m), 4.1 (1H, br m), 3.6 (4H, m), 3.2 (6H,m), 2.8 (2H, m), 1.8 (4H, m).

(CDCl₃) 8.5 (1H, m), 8.1 (2H, s), 8.5 and 8.0 (1H, s), 7.8(1H, m), 7.4(1H, m), 7.3 (2H, m), 6.6 (1H, m), 4.8 and 4.2 (1H, br m), 3.6 (4H, m)3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).

(DMSO) 8.5 (1H, d), 8.4 and 8.2 (1H, s), 7.7 (1H, m), 7.2 (6H, m), 4.8and 4.2 (1H, br m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).

Example 21

The following compounds were prepared

Mp Mp Low High M + H B A Y Q R1 Z 467 4-Cl—Ph PIP SO2 CH23-PyridylCH(CH3)CH2 RH 55 60 456 4-F—Ph PIP SO2 CH2 c hexylC(Me)CH2 RH125 128 440 4-F—Ph PIP SO2 CH2 PhCH2SCH2 RH 130 131 460 4-F—PhPiperidinyl SO2 CH2 2-IndanCH2 RH 64 65 448 4-F—Ph Piperidinyl SO2 CH2(R)-2-PhCH(CH3)CH2 RH 63 64 448 4-F—Ph Piperidinyl SO2 CH2(S)-2-PhCH(CH3)CH2 RH 132 137 484 4-F—Ph PIP SO2 CH2 2-Cl—PhCH(CH3)CH2RH 484 4-F—Ph PIP SO2 CH2 4-Cl—PhCH(CH3)CH2 RH 484 4-F—Ph PIP SO2 CH23-Cl—PhCH(CH3)CH2 RH 469 5-Cl-2-Pyridyl PIP SO2 CH2 2-PyrazineCH(CH3)CH2RH 516 4-F—Ph PIP SO2 CH2 4-Cl—Ph—S—CH(CH3)CH2 RH 466 3-Cl—Ph PIP SO2CH2 (S)-2-PhCH(CH3)CH2 RH 467 5-Cl-2-Pyridyl PIP SO2 CH2(S)-2-PhCH(CH3)CH2 RH 50 51 450 4-F—Ph Piperidinyl SO2 CH22-PyrazineCH(CH3)CH2 RH 60 61 454 4-F—Ph Piperidinyl SO2 CH22-ThiophenylCH(CH3)CH2 RH 82 83 449 4-F—Ph Piperidinyl SO2 CH24-PyridylCH(CH3)CH2 RH 65 66 407 4-F—Ph PIP SO2 CH—Ph RH 91 100 4844-F—Ph PIP SO2 CH2 PhCH2SOCH2 RH 142 145 484 4-F—Ph PIP SO2 CH2PhCH2SOCH2 RH 455 5-Cl-2-Pyridyl PIP SO2 CH2 2-PyrimidinylCH2CH2 RH 4605-cyano-2-pyridyl PIP SO2 CH2 2-PyrimidinylCH2CH2CH2 RH 4445-cyano-2-pyridyl PIP SO2 CH2 PhCH2CH2 RH 464 5-cyano-2-pyridyl PIP SO2CH2 2-ThiophenylCH2CH2CH2 RH 445 5-cyano-2-pyridyl PIP SO2 CH23-PyridylCH2CH2 RH 459 5-cyano-2-pyridyl PIP SO2 CH2 2-PyridylCHHHCH2CH2RH 460 5-cyano-2-pyridyl PIP SO2 CH2 PhCH2OCH2 RH 445 5-cyano-2-pyridylPIP SO2 CH2 2-PyridylCH2CH2 RH 417 5-cyano-2-pyridyl PIP SO2 CH23-Pyridyl RH 498/500 5-Br-2-Pyridyl PIP SO2 CH2 2-PyridylCH2CH2 RH498/500 5-Br-2-Pyridyl PIP SO2 CH2 3-PyridylCH2CH2 RH 497/4995-Br-2-Pyridyl PIP SO2 CH2 PhCH2CH2 RH 513/515 5-Br-2-Pyridyl PIP SO2CH2 PhCH2OCH2 RH 470/472 5-Br-2-Pyridyl PIP SO2 CH2 3-Pyridyl RH 517/5195-Br-2-Pyridyl PIP SO2 CH2 2-ThiophenylCH2CH2CH2 RH 513/5155-Br-2-Pyridyl PIP SO2 CH2 2-PyrimidinylCH2CH2CH2 RH 512/5145-Br-2-Pyridyl PIP SO2 CH2 2-PyridylCH2CH2CH2 RH 436 2-Pyazinyl PIP SO2CH2 2-PyrimidinylCH2CH2CH2 RH 439 2-Pyridyl PIP SO2 CH22-ThiophenylCH2CH2CH2 RH 440 2-Pyrazinyl PIP SO2 CH22-ThiophenylCH2CH2CH2 RH 488.1 5-Cl-2-Pyridyl 4-O-Piperidinyl SO2 CH22-ThiophenylCH2CH2CH2 RH 103 104 484.1 5-Cl-2-Pyridyl 4-O-PiperidinylSO2 CH2 2-ThiophenylCH2CH2CH2 RH 483.3 5-Cl-2-Pyridyl 4-O-PiperidinylSO2 CH2 2-PyridylCH2CH2CH2 RH 508.1 5-Cl-2-Pyridyl 4-O-Piperidinyl SO2CH2 3,4-di-Cl—Ph RH 504/506 5-Cl-2-Pyridyl PIP SO2 CH2 3-Pyridyl-5-bromoRH 123 125 466.3 6-MeO-4-Pyrimidinyl PIP SO2 CH2 PhCH2OCH2 RH 99 101451.3 6-MeO-4-Pyrimidinyl PIP SO2 CH2 2-PyridylCH2CH2 RH 95 99 451.46-MeO-4-Pyrimidinyl PIP SO2 CH2 3-PyridylCH2CH2 RH 156 158 470.36-MeO-4-Pyrimidinyl PIP SO2 CH2 2-ThiophenylCH2CH2CH2 RH 122 124 466.36-MeO-4-Pyrimidinyl PIP SO2 CH2 2-PyrimidinylCH2CH2CH2 RH 465.36-MeO-4-Pyrimidinyl PIP SO2 CH2 2-PyridylCH2CH2CH2 RH PIP = piperazinylZ = reverse hydroxamate group R2 = hydrogen

All compounds were prepared as in Example 1 except those where ring A is4-O-piperidinyl which were prepared as in Example 14.

Example 22

We provide NMR data for the following compounds listed in Example 21:

M452587 - new compound NMR(DMSO) 9.9, 9.6(1H broad s); 8.6(2H m); 8.3and 7.9(1H s); 8.1(1H, dd); 7.3(1H, m) 6.9(1H, d); 4.7 and 4.2(1H broad,m); 3.6(4H, m); 3.4-3.2(6H, m); 2.8(2H, m); 2.1(2H; m).

(DMSO) 9.9 and 9.6(1H, broad s), 8.7(2H, d), 8.3 and 8.0(1H, s), 8.2(1H,d), 7.8(1H, dd), 7.3(1H, m), 6.9(1H, d), 5.1(1H, broad m), 4.7 and4.1(1H, broad m), 3.4(3H, m), 3.1(3H, m), 2.9(2H, m), 2.0(2H, m),1.7(6H, m).

Example 23 Preparation of

To formic acid (4.8 ml) at 0° C. was added acetic anhydride (1.2 ml).After 20 minutes this was added to the hydroxylamine 2 (0.68 g)dissolved in THF (11 ml) and formic acid (5 ml) and the resultingsolution stirred overnight at room temperature. The solvent was removedunder reduced pressure and the residue dissolved in DCM (100 ml), washedwith saturated sodium bicarbonate solution (2×100 ml), dried (MgSO₄) andevaporated to dryness. The residue was purified by flash columnchromatography eluting with dichloromethane/methanol (96:4) to give theproduct (0.41 g) as a gum. NMR CDCl₃ δ 9.7 (br s, 1H)*; 9.2 (br s, 1H)*;8.4 (s, 1H)*; 8.0 (s, 1H)*; 7.5-7.2 (m, 5H); 7.0-6.8 (m, 4H); 5.7 (m,1H)*; 5.4 (m, 1H)*; 3.9-3.4 (m, 5H); 3.3 (m, 1H)*; 3.2-2.9 (m, 4H); 2.8(m, 1H)*. MS for C₂₀H₂₂FN₃O₃ (M+H) calcd 372, found 372.

*rotameric signals

To 1-(4-fluorophenyl)piperazine (1.00 g) dissolved in DCM (10 ml) wasadded cinnamoyl chloride (0.85 g) in DCM (10 ml) followed bytriethylamine (1.55 ml). The solution was stirred at room temperatureovernight. It was then separated between DCM (150 ml) and water (100ml), the organic layer was then washed with water (100 ml), dried(MgSO₄) and evaporated to dryness to give a cream solid which wastriturated with diethyl ether (10 ml) to give 1 (1.20 g) as a whitesolid. NMR CDCl₃ δ 7.7 (d, 1H); 7.5 (m, 2H); 7.4 (m, 3H); 7.0-6.9 (m,5H); 4.0-3.8 (m, 4H); 3.1 (m, 4H). MS for C₁₉H₁₉FN₂O (M+H) calc 311,found 311.

To the amide (2.00 g) dissolved in THF (40 ml) was added hydroxylamine(1 ml, 50% aqueous solution). The solution was stirred at roomtemperature for 48 hours. The solvent was then evaporated under reducedpressure, toluene was added (50 ml) and this was also evaporated underreduced pressure. The residue was triturated with dichloromethane/methanol (98:2) and the mother liquor purified by flash columnchromatography eluting with dichloromethane/methanol (98:2) to give 2(0.70 g) as a gum. NMR CDCl₃ δ 7.5-7.2 (m, 5H); 7.0-6.9 (m, 2H); 6.9-6.8(m, 2H); 4.5 (dd, 1H); 3.8-3.7 (m, 2H); 3.6-3.5 (m, 2H); 3.1-2.8 (m,5H); 2.7 (dd, 1H). MS for C₁₉H₂₂FN₃O₂ (M+H) calcd 344, found 344.

We claim:
 1. A compound of the formula I

wherein ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl ring comprising up to 12 ring atoms andcontaining one or more heteroatoms independently chosen from N, O, andS; alternatively ring B may be biphenyl; ring B may optionally be linkedto ring A by a C₁₋₄ alkyl or a C₁₋₄alkoxy chain linking the 2-positionof ring B with a carbon atom alpha to X₂; each R³ is independentlyselected from hydrogen, halogen, NO₂, COOR wherein R is hydrogen or C₁₋₆alkyl, CN, CF₃, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —SO—C₁₋₆ alkyl, —SO₂—C₁₋₆alkyl, C₁₋₆alkoxy and up to C₁₀ aryloxy, n is 1, 2, or 3; P is—(CH₂)_(n)— wherein n=0, 1, 2; or P is an alkene or alkyne chain of upto six carbon atoms; or P may be selected from —CO—N(R₆)—, —N(R₆)—CO—,—SO₂—N(R₆)—, and —N(R₆)—SO₂—, and R₆ is hydrogen, C₁₋₆ alkyl, up to C₁₀aralkyl or up to C₉heteroalkyl; Ring A is a piperazine ring and mayoptionally be mono- or di-substituted by optionally substituted C₁₋₆alkyl or C₁₋₆alkoxy, each substituent being independently selected fromhalogen, C₁₋₆ alkyl, or an oxo group; X₁ and X₂ are each N; Y isselected from —SO₂— and —CO—; Z is —N(OH)CHO and Q is selected from—CH(R₆)—, —CH(R₆)—CH₂—, and —N(R₆)—CH₂—; R¹ is H, C₁₋₆ alkyl, C₅₋₇cycloalkyl, up to C₁₀ aryl, up to C₁₀ heteroaryl, up to C₁₂ aralkyl, orup to C₁₂ heteroarylalkyl, all optionally substituted by up to threegroups independently selected from NO₂, CF₃, halogen, C₁₋₄ alkyl,carboxy(C₁₋₄)alkyl, up to C₆ cycloalkyl, C₁₋₄ alkyl substituted with—OR⁴, SR⁴ (and its oxidised analogues), or C₁₋₄ alkyl-Y—NR⁴, or R¹ is2,3,4,5,6-pentafluorophenyl; R⁴ is hydrogen, C₁₋₆ alkyl, up to C₁₀ aryl,up to C₁₀ heteroaryl, or up to C₉ aralkyl, each independently optionallysubstituted by halogen, NO₂, CN, CF₃, C₁₋₆ alkyl, —S—C₁₋₆ alkyl,—SO—C₁₋₆ alkyl, —SO₂—C₁₋₆ alkyl, or C₁₋₆alkoxy; R² is H, C₁₋₆ alkyl, ortogether with R¹ forms a carbocyclic or heterocyclic spiro 5, 6, or 7membered ring, the latter containing at least one heteroatom selectedfrom N, O, and S; also the group Q can be linked to either R¹ or R² toform a 5, 6, or 7 membered alkyl or heteroalkyl ring comprising one ormore of O, S, and N; and wherein any alkyl groups outlined above may bestraight chain or branched; or a pharmaceutically acceptable salt or anin vivo hydrolysable precursor thereof.
 2. A compound as claimed inclaim 1, wherein: ring A is optionally mono- or di-substituted byoptionally substituted C₁₋₆ alkyl or C₁₋₆alkoxy, each substituent beingindependently selected from halogen, —C₁₋₆ alkyl, or an oxo group; R³ ishydrogen, halogen, NO₂, CF₃, C₁₋₄ alkyl, and C₁₋₄alkoxy, n is 1 or 2;ring B is monocyclic or bicyclic aryl, aralkyl, or heteroaryl having upto 10 ring atoms; P is —(CH₂)_(n)— wherein n is 0 or 1, —O—, or—CO—N(R₆)—; R¹ is hydrogen, C₁₋₆ alkyl, C₅₋₇ cycloalkyl, up to C₁₂aralkyl, up to C₁₁ heteroarylalkyl, or up to C₁₀ aryl or C₁₀ heteroaryl,all optionally substituted by up to three halogen atoms, or by CF₃; R²is hydrogen, or together with R¹ represents a carbocyclic orheterocyclic spiro 5- or 6-membered ring; R⁴ is up to C₁₀ aryloptionally substituted by halogen, NO₂, CN, CF₃, C₁₋₆ alkyl, —S—C₁₋₆alkyl, —SO—C₁₋₆ alkyl, —SO₂—C₁₋₆ alkyl, or C₁₋₆alkoxy; or apharmaceutically acceptable salt or an in vivo hydrolysable precursorthereof.
 3. A compound as claimed in claim 1, wherein: R³ is hydrogen,halogen, NO₂, CF₃, methyl, ethyl, methoxy, or ethoxy; ring B is amonocyclic aryl, aralkyl, or heteroaryl ring having up to 7 ring atoms;P is a direct bond; Y is —SO₂—; Q is —CH₂—; R¹ is phenyl,4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl,benzyloxymethyl, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl,2-pyridylethyl, 3-pyridylethyl, thiophenylpropyl, bromothiophenyl,2-pyrimidinylethyl, 2-pyrimidinylpropyl, pyridylpropyl, or together withR² is spirocyclohexane or spiro-4-pyran; R² is hydrogen; Z is —N(OH)CHO;or a pharmaceutically acceptable salt or an in vivo hydrolysableprecursor thereof.
 4. A compound as claimed in any one of the previousclaims, wherein ring B is selected from an optionally substitutedphenyl, pyridyl, or pyrimidine ring; or a pharmaceutically acceptablesalt or an in vivo hydrolysable precursor thereof.
 5. A compound asclaimed in claim 1, wherein ring B substituted by (R³)_(n) is phenyl,3-methylhenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, or 5-chloro-2-pyridyl; P is a direct bond; Y is SO₂,Q is —CH₂—, and Z is —N(OH)CHO; or a pharmaceutically acceptable salt oran in vivo hydrolysable precursor thereof.
 6. A compound as claimed inclaim 1, wherein ring B is phenyl, 3-methylphenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl ring, or5-chloro-2-pyridyl; P is a direct bond; Y is SO₂; Q is —CH₂—; Z is—N(OH)CHO; and R¹ is phenyl, phenbutylene, phenisopropylene,2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene,4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene; or apharmaceutically acceptable salt or an in vivo hydrolysable precursorthereof.
 7. A compound as claimed in claim 1, wherein ring B is phenylmonosubstituted by chlorine or fluorine, P is a direct bond, Y is SO₂, Qis —CH₂—, Z is —CONHOH and R¹ is hydrogen, i-butyl, orspirotetrahydropyranyl; or a pharmaceutically acceptable salt, or an invivo hydrolysable precursor thereof.
 8. A compound as claimed in claim1, wherein a ring substituent on ring A is an oxo group adjacent to aring nitrogen atom.
 9. A process for preparing a compound as claimed inclaim 1, or a pharmaceutically acceptable salt, or an in vivohydrolysable ester thereof, which process comprises a) reacting acompound of the formula (II), or a pharmaceutically acceptable salt, oran in vivo hydrolysable ester thereof, with a compound of the formula(III)

wherein X₁ ^(I) represents X₁, a precursor of X₁, or an activated formof X₁ suitable for reaction with Y^(I); Y^(I) represents Y, a precursorof Y, or an activated form of Y suitable for reaction with X₁ ^(I);Z^(I) represents a protected form of Z, a precursor of Z, or anactivated form of Z; and where Q is —(CH₂)(R₆)—; then by reacting acompound of the formula IX with an appropriate compound of the formulaR¹—CO—R² to yield an alkene of the formula X, which is then converted toa compound of the formula XI wherein Z* is a hydroxylamine precursor ofthe group Z, and then converting Z* to the group Z, all as set outbelow:

 or b) reacting a compound of the formula (IV), or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester thereof, with acompound of the formula (V):

wherein B^(I) represents a suitable ring function or substituent groupfor reaction with P^(I); Z^(I) is as hereinbefore defined; and P^(I)represents a suitably activated form of the linker P for reaction withB^(I) or P^(I) may be present on ring A rather than ring B^(I) or, asrequired, the linker P may be formed by appropriate reaction ofprecursor groups P″ and P′″ provided on rings B^(I) and A respectively,or vice versa.
 10. A pharmaceutical composition which comprises acompound as claimed in claim 1, or a pharmaceutically acceptable salt,or an in vivo hydrolysable ester thereof, and a pharmaceuticallyacceptable carrier.
 11. A method of preparing a medicament including acompound as claimed in claim 1, or a pharmaceutically acceptable salt,or an in vivo hydrolysable precursor thereof, comprising combining thecompound with a pharmaceutically acceptable diluent or carrier.
 12. Amethod of treating a metalloproteinase mediated disease condition whichcomprises administering to a warm-blooded animal a therapeuticallyeffective amount of a compound as claimed in claim 1, or apharmaceutically acceptable salt, or an in vivo hydrolysable esterthereof.
 13. A method of treating arthritis, comprising administering atherapeutic amount of a compound as claimed in claim 1, or apharmaceutically acceptable salt, or an in vivo hydrolysable precursorthereof, to a subject in need of such treatment.
 14. A method oftreating atherosclerosis, comprising administering a therapeutic amountof a compound as claimed in claim 1, or a pharmaceutically acceptablesalt, or an in vivo hydrolysable precursor thereof, to a subject in needof such treatment.